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1.
Clin Transl Sci ; 14(2): 481-486, 2021 03.
Article in English | MEDLINE | ID: mdl-33222389

ABSTRACT

Mechanical ventilation (MV) is a life-saving intervention for many critically ill patients. Unfortunately, prolonged MV results in the rapid development of inspiratory muscle weakness due to diaphragmatic atrophy and contractile dysfunction (termed ventilator-induced diaphragm dysfunction (VIDD)). Although VIDD is a major risk factor for problems in weaning patients from MV, a standard therapy to prevent VIDD does not exist. However, emerging evidence suggests that pharmacological blockade of angiotensin II type 1 receptors (AT1Rs) protects against VIDD. Nonetheless, the essential characteristics of AT1R blockers (ARBs) required to protect against VIDD remain unclear. To determine the traits of ARBs that are vital for protection against VIDD, we compared the efficacy of two clinically relevant ARBs, irbesartan and olmesartan; these ARBs differ in molecular structure and effects on AT1Rs. Specifically, olmesartan blocks both angiotensin II (AngII) binding and mechanical activation of AT1Rs, whereas irbesartan prevents only AngII binding to AT1Rs. Using a well-established preclinical model of prolonged MV, we tested the hypothesis that compared with irbesartan, olmesartan provides greater protection against VIDD. Our results reveal that irbesartan does not protect against VIDD whereas olmesartan defends against both MV-induced diaphragmatic atrophy and contractile dysfunction. These findings support the hypothesis that olmesartan is superior to irbesartan in protecting against VIDD and are consistent with the concept that blockade of mechanical activation of AT1Rs is a required property of ARBs to shield against VIDD. These important findings provide a foundation for future clinical trials to evaluate ARBs as a therapy to protect against VIDD.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/administration & dosage , Diaphragm/pathology , Respiration, Artificial/adverse effects , Animals , Atrophy/etiology , Atrophy/prevention & control , Diaphragm/drug effects , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Humans , Imidazoles/administration & dosage , Irbesartan/administration & dosage , Rats , Respiration, Artificial/instrumentation , Tetrazoles/administration & dosage , Ventilators, Mechanical/adverse effects
2.
ESC Heart Fail ; 5(3): 222-230, 2018 06.
Article in English | MEDLINE | ID: mdl-29469206

ABSTRACT

AIMS: Sleep-disordered breathing (SDB) is a highly prevalent co-morbidity in patients with chronic heart failure (CHF) and can play a detrimental role in the pathophysiology course of CHF. However, the best way to manage SDB in CHF remains a matter of debate. Sacubitril-valsartan has been included in the 2016 European Society of Cardiology guidelines as an alternative to angiotensin-converting enzyme inhibitors to further reduce the risk of progression of CHF, CHF hospitalization, and death in ambulatory patients. Sacubitril and valsartan are good candidates for correcting SDB of CHF patients because their known mechanisms of action are likely to counteract the pathophysiology of SDB in CHF. METHODS AND RESULTS: The ENTRESTO-SAS trial is a 3-month, multicentric, prospective, open-label real-life cohort study. Patients eligible for sacubitril-valsartan treatment (i.e. adults with left ventricular ejection fraction ≤35%, who remain symptomatic despite optimal treatment with an angiotensin-converting enzyme inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist) will be evaluated before and after 3 months of treatment (nocturnal ventilatory polygraphy, echocardiography, laboratory testing, and quality-of-life and SDB questionnaires). The primary outcome is the change in the Apnoea-Hypopnoea Index, before and after 3 months of treatment. One hundred twenty patients are required to detect a significant 20% improvement of the Apnoea-Hypopnoea Index with a power of 90% at an alpha risk of 5%. CONCLUSIONS: In the context of the SERVE-HF study, physicians are waiting for new trials and alternative therapies. We sought to assess in the ENTRESTO-SAS trial whether sacubitril-valsartan could improve the outcome of SDB in CHF patients.


Subject(s)
Aminobutyrates/administration & dosage , Heart Failure/drug therapy , Sleep Apnea Syndromes/drug therapy , Stroke Volume/physiology , Tetrazoles/administration & dosage , Angiotensin Receptor Antagonists/administration & dosage , Biphenyl Compounds , Dose-Response Relationship, Drug , Drug Combinations , Echocardiography , Female , Follow-Up Studies , Heart Failure/complications , Heart Failure/physiopathology , Humans , Male , Neprilysin , Polysomnography , Prospective Studies , Sleep Apnea Syndromes/complications , Time Factors , Treatment Outcome , Valsartan
3.
J Med Microbiol ; 67(2): 265-271, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29300156

ABSTRACT

PURPOSE: Glycopeptides are widely used for the treatment of meticillin-resistant Staphylococcus aureus (MRSA) infections. Although difficult to detect, isolates with reduced (GISA), hetero (hGISA) or complete (GRSA) resistance to glycopeptides are increasingly reported. Optimal therapy for such strains is unknown. We compared the in vitro and in vivo activity of tedizolid (TED), a recently licensed oxazolidonone, with vancomycin (VAN) and teicoplanin (TEIC) combined with fusidic acid (FD) or rifampicin (RIF) against S. aureus (SA) with reduced susceptibility to glycopeptides. METHODS: Susceptibility was determined for six (GISA, hGISA and GRSA) reference strains and 72 clinical MRSA isolates screened for hGISA/GISA-like phenotypes. Synergy and bactericidal activity were assessed using chequerboard and time-kill assays. The G. mellonella wax moth caterpillar model was used to measure the activity of TED and the combinations in vivo. RESULTS: Glycopeptide MICs (VAN/TEIC) ranged from 0.5-8/4 and 0.125-1 for TED. No significant synergy was noted when VAN/TEIC were combined with either RIF or FD. Time-kill assays confirmed that TED was bacteriostatic but superior to VAN and TEIC against GISA strains. In G. mellonella TED was more effective than TEIC monotherapy versus GISA strains. The combination of TEIC with RIF was the most effective combination overall, both in vitro and in vivo. CONCLUSIONS: TED had good in vitro activity versus MRSA including those with reduced susceptibility to glycopeptides. Although bacteriostatic, it was effective in the G. mellonella model and superior to TEIC in the treatment of GISA. Although this supports the use of TED for MRSA and GISA, the TEIC/RIF combination also warrants further study.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Oxazolidinones/therapeutic use , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Teicoplanin/therapeutic use , Tetrazoles/therapeutic use , Vancomycin/therapeutic use , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Drug Therapy, Combination , Humans , Larva/microbiology , Lepidoptera/microbiology , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Oxazolidinones/administration & dosage , Oxazolidinones/pharmacology , Staphylococcal Infections/microbiology , Teicoplanin/administration & dosage , Teicoplanin/pharmacology , Tetrazoles/administration & dosage , Tetrazoles/pharmacology , Vancomycin/administration & dosage , Vancomycin/pharmacology
4.
Vasa ; 46(6): 471-475, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28753096

ABSTRACT

BACKGROUND: Proper management of patients with thromboangiitis obliterans (TAO) or cannabis-associated arteritis (CAA), presenting with critical lower limb ischaemia (CLI) remains controversial, and data are limited. PATIENTS AND METHODS: Patients with TAO or CAA presenting with CLI between 2011 and 2016 were retrospectively evaluated. Patients requiring primary intervention were excluded. Conservative treatment included: (a) weight-adjusted bemiparin plus six hours/day intravenous iloprost for 28 days, (b) aspirin (100 mg/day) plus cilostazol (100 mg twice/day) after discharge, and (c) strict recommendations/monitoring for smoking cessation. Main outcomes included symptom recession, ankle-brachial index (ABI) improvement, and healing of lesions at the time of discharge as well as amputation, revascularization, and abstinence rate during follow-up. RESULTS: Overall, 23 patients (TAO: 15; CAA: 8) were included within six years, none of the patients reported any other factor than smoking. All patients presented with rest pain and 12 patients with ulcer or necrotic lesions. Mean ABI measurement at presentation was 0.46 ± 0.2, after 28 days of treatment, all patients showed improvement regarding clinical picture and ABI measurement (0.54 ± 0.1; p < 0.05). During follow-up, only three patients underwent bypass surgery and two patients underwent major amputation, although the smoking abstinence rate was very low (13 %). CONCLUSIONS: Intravenous iloprost plus bemiparin for 28 days together with per os aspirin plus cilostazol seem to produce promising results in patients with TAO/CAA, treated for CLI, even with a low smoking abstinence rate. However, larger series are needed to further evaluate inter-group differences and potential prognostic factors.


Subject(s)
Arteritis/drug therapy , Cardiovascular Agents/administration & dosage , Ischemia/drug therapy , Lower Extremity/blood supply , Marijuana Abuse/complications , Marijuana Smoking/adverse effects , Smoking Cessation , Smoking/adverse effects , Thromboangiitis Obliterans/drug therapy , Adult , Amputation, Surgical , Ankle Brachial Index , Anticoagulants/administration & dosage , Arteritis/diagnosis , Arteritis/etiology , Aspirin/administration & dosage , Cardiovascular Agents/adverse effects , Cilostazol , Critical Illness , Drug Therapy, Combination , Female , Heparin, Low-Molecular-Weight/administration & dosage , Humans , Iloprost/administration & dosage , Infusions, Intravenous , Ischemia/diagnosis , Ischemia/etiology , Limb Salvage , Male , Marijuana Abuse/diagnosis , Marijuana Abuse/therapy , Marijuana Smoking/prevention & control , Middle Aged , Platelet Aggregation Inhibitors/administration & dosage , Recurrence , Remission Induction , Retrospective Studies , Risk Factors , Tetrazoles/administration & dosage , Thromboangiitis Obliterans/diagnosis , Thromboangiitis Obliterans/etiology , Time Factors , Treatment Outcome , Vasodilator Agents/administration & dosage
5.
Blood Press ; 26(5): 284-293, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28524699

ABSTRACT

BACKGROUND: Data are sparse regarding ambulatory blood pressure (BP) reduction of up-titration from a standard dose to a high dose in both nifedipine controlled-release (CR) and amlodipine. This was a prospective, randomized, multicenter, open-label trial. PATIENTS AND METHODS: Fifty-one uncontrolled hypertensives medicated by two or more antihypertensive drugs including a renin-angiotensin system inhibitor and a calcium antagonist were randomly assigned to either the nifedipine CR (80 mg)/candesartan (8 mg) group or the amlodipine (10 mg)/candesartan (8 mg) group. RESULTS: The changes in 24-hr BP were comparable between the groups. The nifedipine group demonstrated a significant decrease in their urinary albumin creatinine ratio, whereas the amlodipine group demonstrated a significant decrease in their NTproBNP level. However, there was no significant difference in any biomarkers between the two groups. CONCLUSION: Nifedipine showed an almost equal effect on ambulatory blood pressure as amlodipine. Their potentially differential effects on renal protection and NTproBNP should be tested in larger samples.


Subject(s)
Amlodipine/therapeutic use , Antihypertensive Agents/therapeutic use , Benzimidazoles/therapeutic use , Calcium Channel Blockers/therapeutic use , Hypertension/drug therapy , Nifedipine/therapeutic use , Tetrazoles/therapeutic use , Aged , Aged, 80 and over , Amlodipine/administration & dosage , Antihypertensive Agents/administration & dosage , Benzimidazoles/administration & dosage , Biphenyl Compounds , Blood Pressure/drug effects , Blood Pressure Monitoring, Ambulatory , Calcium/metabolism , Calcium Channel Blockers/administration & dosage , Delayed-Action Preparations/chemistry , Female , Humans , Hypertension/physiopathology , Male , Middle Aged , Nifedipine/administration & dosage , Prospective Studies , Tetrazoles/administration & dosage
6.
Drug Des Devel Ther ; 11: 65-82, 2017.
Article in English | MEDLINE | ID: mdl-28053508

ABSTRACT

Tedizolid phosphate has high activity against the Gram-positive microorganisms mainly involved in acute bacterial skin and skin structure infections, such as strains of Staphylococcus aureus (including methicillin-resistant S. aureus strains and methicillin-sensitive S. aureus strains), Streptococcus pyogenes, Streptococcus agalactiae, the Streptococcus anginosus group, and Enterococcus faecalis, including those with some mechanism of resistance limiting the use of linezolid. The area under the curve for time 0-24 hours/minimum inhibitory concentration (MIC) pharmacodynamic ratio has shown the best correlation with the efficacy of tedizolid, versus the time above MIC ratio and the maximum drug concentration/minimum inhibitory concentration ratio. Administration of this antibiotic for 6 days has shown its noninferiority versus administration of linezolid for 10 days in patients with skin and skin structure infections enrolled in two Phase III studies (ESTABLISH-1 and ESTABLISH-2). Tedizolid's more favorable safety profile and dosage regimen, which allow once-daily administration, versus linezolid, position it as a good therapeutic alternative. However, whether or not the greater economic cost associated with this antibiotic is offset by its shorter treatment duration and possibility of oral administration in routine clinical practice has yet to be clarified.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Oxazolidinones/therapeutic use , Skin Diseases, Bacterial/drug therapy , Skin Diseases, Bacterial/microbiology , Tetrazoles/therapeutic use , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Enterococcus faecalis/drug effects , Humans , Microbial Sensitivity Tests , Oxazolidinones/administration & dosage , Oxazolidinones/pharmacology , Streptococcus/drug effects , Tetrazoles/administration & dosage , Tetrazoles/pharmacology
7.
PLoS One ; 12(1): e0168582, 2017.
Article in English | MEDLINE | ID: mdl-28045910

ABSTRACT

BACKGROUND: Antihypertensive treatment mitigates the progression of chronic kidney disease. Here, we comparatively assessed the effects of antihypertensive agents in normotensive and hypertensive diabetic patients with microalbuminuric kidney disease. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) comparing oral antihypertensive agents in adult diabetic patients with microalbuminuria. The primary efficacy outcome was reduction in albuminuria, and the primary safety outcomes were dry cough, presyncope, and edema. Random-effects pairwise and Bayesian network meta-analyses were performed to produce outcome estimates for all RCTs, only hypertensive RCTs, or only normotensive RCTs. Surface under the cumulative ranking (SUCRA) probability rankings were calculated for all outcomes. Sensitivity analyses on type 2 diabetes status, age, or follow-up duration were also performed. RESULTS: A total of 38 RCTs were included in the meta-analyses. The angiotensin-converting enzyme inhibitor-calcium channel blocker (ACEI-CCB) combination therapy of captopril+diltiazem was most efficacious in reducing albuminuria irrespective of blood pressure status. However, the ACEI-angiotensin receptor blocker (ACEI-ARB) combination therapy of trandolapril+candesartan was the most efficacious in reducing albuminuria for normotensive patients, while the ACEI-CCB combination therapy of fosinopril+amlodipine was the most efficacious in reducing albuminuria for hypertensive patients. The foregoing combination therapies displayed inferior safety profiles relative to ACEI monotherapy with respect to dry cough, presyncope, and edema. With respect to type 2 diabetic patients with microalbuminuria, the Chinese herbal medicine Tangshen formula followed by the ACEI ramipril were the most efficacious in reducing albuminuria. CONCLUSIONS: Trandolapril+candesartan appears to be the most efficacious intervention for reducing albuminuria for normotensive patients, while fosinopril+amlodipine appears to be the most efficacious intervention for reducing albuminuria for hypertensive patients. For practitioners opting for monotherapy, our SUCRA analysis supports the use of trandolapril and fosinopril in normotensive and hypertensive adult diabetic patients with microalbuminuria, respectively.


Subject(s)
Albuminuria/drug therapy , Antihypertensive Agents/therapeutic use , Diabetes Mellitus, Type 2/therapy , Kidney Diseases/therapy , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Bayes Theorem , Benzimidazoles/administration & dosage , Biphenyl Compounds , Follow-Up Studies , Fosinopril/administration & dosage , Humans , Hypertension/drug therapy , Indoles/administration & dosage , Kidney Diseases/complications , Middle Aged , Patient Safety , Probability , Randomized Controlled Trials as Topic , Tetrazoles/administration & dosage , Treatment Outcome , Young Adult
8.
Zhongguo Zhen Jiu ; 37(12): 1280-4, 2017 Dec 12.
Article in Chinese | MEDLINE | ID: mdl-29354992

ABSTRACT

OBJECTIVE: To compare the efficacy differences between moxibustion at Geshu (BL 17) and oral administration of cilostazol on diabetic limb arterial obliteration (DLAO) at early stage as well as the impacts on hemorheology and arterial inner dimension of lower extremity. METHODS: Seventy patients of DLAO at early stage were randomly divided into an observation group and a control group, 35 cases in each one. The two groups were treated with regular treatment of blood glucose and blood lipid. The patients in the control group was treated with oral administration of cilostazol, 50 mg, twice a day; the patients in the observation group were treated with moxibustion at Geshu (BL 17), once a day. The consecution treatment of two weeks constituted one session, and totally 4 sessions were given. The total syndrome score, hemorheology index (including low and high shear viscosity of blood, plasma viscosity, hematocrit and erythrocyte aggregation index) and arterial inner dimension of lower extremity (including popliteal artery, posterior tibial artery and dorsalis pedis artery) were compared before and after treatment. RESULTS: Compared with those before treatment, the total syndrome score, hemorheology index and arterial inner dimension of lower extremity were significantly improved after treatment in the two groups (all P<0.05). The total syndrome score, hemorheology index in the observation group were superior to those in the control group (all P<0.05), but the improvement of arterial inner dimension of lower extremity was not significantly different between the two groups (P>0.05). After treatment, the total effective rate was 91.4% (32/35) in the observation group, which was significantly superior to 85.7% (30/35) in the control group (P<0.05). CONCLUSION: Moxibustion at Geshu (BL 17) is superior to oral administration of cilostazol for DLAO at early stage, which could effectively improve the clinical symptoms, blood flow and blood vessel and increase the blood flow of lower limb.


Subject(s)
Acupuncture Points , Lower Extremity/blood supply , Moxibustion/methods , Tetrazoles/administration & dosage , Administration, Oral , Blood Glucose , Cilostazol , Constriction, Pathologic/etiology , Constriction, Pathologic/therapy , Diabetes Mellitus/therapy , Humans , Regional Blood Flow
9.
J Clin Pharm Ther ; 41(6): 695-702, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27670639

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: The nifedipine gastrointestinal therapeutic system (GITS)/candesartan cilexetil (N/C) combination was demonstrated to be an effective, well-tolerated antihypertensive therapy in a short-term study. The current study investigated the long-term safety and efficacy of a fixed-dose combination (FDC) of N/C therapy in moderate-to-severe essential hypertension. METHODS: A multinational, 70-centre, open-label study of N/C treatment for 28 or 52 weeks at a target dose of N60 mg/C32 mg. The primary assessment included the incidence of treatment-emergent adverse events (TEAEs). Efficacy assessments included change from baseline in systolic and diastolic blood pressure (BP). RESULTS AND DISCUSSION: A total of 508 patients were enrolled, with 417 (82·1%) completing week 28 of treatment. Of these, 200 patients continued treatment, as planned, to week 52, with 193 (96·5%) completing this period. At least one TEAE or drug-related TEAE were reported in 76·8% and 45·3% patients up to week 28, and in 80·7% and 46·9% up to week 52/end of study. Most TEAEs and drug-related TEAEs to week 52 (93·9% and 95·4%, respectively) were mild or moderate in intensity. Rates of drug-related serious AEs were low (0·6%). TEAE-related discontinuations occurred in 10% patients before week 28 and in no additional patients thereafter. N/C provided substantial, sustained reductions in mean systolic and diastolic BP from baseline: 30·1 ± 18·4 and 12·8 ± 10·7 mmHg, respectively, at week 52. WHAT IS NEW AND CONCLUSIONS: Nifedipine GITS/candesartan cilexetil FDC at the target dose of 60 mg/32 mg was well tolerated for a study duration up to 52 weeks and provided sustained reductions in systolic and diastolic BP.


Subject(s)
Antihypertensive Agents/administration & dosage , Benzimidazoles/administration & dosage , Biphenyl Compounds/administration & dosage , Hypertension/drug therapy , Nifedipine/administration & dosage , Tetrazoles/administration & dosage , Aged , Blood Pressure , Drug Therapy, Combination/methods , Essential Hypertension , Female , Humans , Male , Middle Aged
10.
Drugs ; 76(10): 1015-22, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27272555

ABSTRACT

Fimasartan is the ninth, and most recent, angiotensin II receptor antagonist approved as an antihypertensive agent. Fimasartan, a pyrimidin-4(3H)-one derivative of losartan with the imidazole ring replaced, which enables higher potency and longer duration than losartan. Fecal elimination and biliary excretion are the predominant elimination pathways of fimasartan and the urinary excretion was found to be less than 3 % 24 h after administration. Fimasartan is primarily catabolized by cytochrome P450 isoform 3A and no significant drug interaction was observed when used in combination with hydrochlorothiazide, amlodipine, warfarin, or digoxin. Fimasartan at a dosage range of 60-120 mg once daily showed an antihypertensive effect over 24 h. In a large, population-based observational study, fimasartan showed an excellent safety profile. Anti-inflammatory and organ-protecting effects of fimasartan have been shown in various preclinical studies, including aortic balloon injury, myocardial infarct ischemia/reperfusion, doxorubicin cardiotoxicity, and ischemic stroke models.


Subject(s)
Angiotensin II Type 2 Receptor Blockers/therapeutic use , Antihypertensive Agents/therapeutic use , Biphenyl Compounds/therapeutic use , Hypertension/drug therapy , Pyrimidines/therapeutic use , Tetrazoles/therapeutic use , Angiotensin II Type 2 Receptor Blockers/administration & dosage , Angiotensin II Type 2 Receptor Blockers/adverse effects , Angiotensin II Type 2 Receptor Blockers/pharmacokinetics , Animals , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/adverse effects , Antihypertensive Agents/pharmacokinetics , Biphenyl Compounds/administration & dosage , Biphenyl Compounds/adverse effects , Biphenyl Compounds/pharmacokinetics , Clinical Trials as Topic , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Drug Therapy, Combination , Humans , Hypertension/metabolism , Molecular Structure , Observational Studies as Topic , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Tetrazoles/administration & dosage , Tetrazoles/adverse effects , Tetrazoles/pharmacokinetics , Treatment Outcome
11.
Eur J Heart Fail ; 18(9): 1193-202, 2016 09.
Article in English | MEDLINE | ID: mdl-27170530

ABSTRACT

AIMS: To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%). METHODS AND RESULTS: A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'. CONCLUSIONS: Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group.


Subject(s)
Aminobutyrates/administration & dosage , Angiotensin Receptor Antagonists/administration & dosage , Heart Failure/drug therapy , Neprilysin/antagonists & inhibitors , Tetrazoles/administration & dosage , Aged , Biphenyl Compounds , Double-Blind Method , Drug Combinations , Female , Humans , Hyperkalemia/chemically induced , Hypotension/chemically induced , Male , Middle Aged , Renal Insufficiency/chemically induced , Treatment Outcome , Valsartan
12.
J Manag Care Spec Pharm ; 22(3): 255-62, 2016 Mar.
Article in English | MEDLINE | ID: mdl-27003555

ABSTRACT

BACKGROUND: Lack of adherence to prescribed therapies is often a cause of suboptimal blood pressure control in patients with hypertension. To enhance patients' adherence to treatment, fixed-dose combinations of active substances with complementary mechanisms of action have been developed. An angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker (ARB) is often combined with a calcium channel blocker. Olmesartan is the most used ARB in combination therapy. In Italy, in September 2011, a fixed-dose combination of olmesartan/amlodipine (olmesartan/amlodipine 20/5 mg, 40/5 mg, or 40/10 mg) was introduced to treat patients with hypertension for whom control of blood pressure is not reached with either olmesartan or amlodipine alone. Prior research on adherence to olmesartan/amlodipine combinations was carried out in local contexts (e.g., claims databases of Italian regions or local health authorities), and/or it was limited by the fact that adherence was assessed against monotherapies already known for their low compliance profile, such as diuretics. OBJECTIVE: To compare adherence with olmesartan/amlodipine fixed-dose combination (FDC) and extemporaneous combination in primary care in Italy. METHODS: A nationwide, population-based study was conducted by using the Health Search IMS Health Longitudinal Patient Database. Patients aged > 17 years, affected by hypertension and treated with the FDC or extemporaneous combination of olmesartan/amlodipine, were identified. Adherence to these 2 therapeutic regimens was estimated by calculating the proportion of days covered (PDC). Patients were classified into 3 levels of adherence: high (PDC ≥ 80%), intermediate (PDC = 40%-79%), or low (PDC < 40%). RESULTS: In the 6-month follow-up, FDC showed higher adherence compared with an extemporaneous combination (55.1% vs. 15.9%, P < 0.001). This difference was confirmed in a multivariable logistic regression model clustered on patient identifier (odds ratio = 6.65; 95% CI = 3.10-14.26; P < 0.001). The proportion of patients adherent to FDC varied from 60.4% for the 40/5 mg formulation to 47.5% for the 40/10 mg formulation. CONCLUSIONS: These findings suggest that higher adherence may be achieved with FDCs than with extemporaneous combinations. To improve the degree of adherence, general practitioners may consider prescribing fixed combinations of antihypertensive agents as soon as monotherapies fail to achieve the expected therapeutic objective.


Subject(s)
Amlodipine/administration & dosage , Drug Therapy, Combination , Imidazoles/administration & dosage , Medication Adherence , Tetrazoles/administration & dosage , Aged , Antihypertensive Agents/administration & dosage , Blood Pressure/drug effects , Female , Humans , Hypertension/drug therapy , Male
13.
J Clin Pharmacol ; 56(9): 1120-9, 2016 09.
Article in English | MEDLINE | ID: mdl-26829251

ABSTRACT

DISTINCT was an 8-week, double-blind, randomized study to investigate the antihypertensive efficacy and safety of various nifedipine gastrointestinal treatment system (GITS)/candesartan cilexetil (N/C) dose combinations, vs respective monotherapies or placebo, in patients with diastolic blood pressure (DBP) ≥95 to <110 mm Hg. The current prespecified analysis compared BP reduction in participants with mild vs moderate baseline hypertension (ie, systolic [S]BP <160 mm Hg vs ≥160 mm Hg and DBP <100 mm Hg vs ≥100 mm Hg). A total of 1362 patients were analyzed by descriptive statistics. In all patient subgroups investigated, the NC combinations (ie, N: 20, 30, or 60 mg; C: 4, 8, 16, or 32 mg daily) provided greater SBP and DBP lowering and higher rates of BP control (defined as BP <140/90 mm Hg) than respective monotherapies or placebo, with greatest absolute BP reductions observed in the moderately elevated SBP or DBP subgroups. A trend to dose-response relationship was observed in each subgroup. In each SBP and DBP subgroup, treatment-related vasodilatory events (flushing, headache, or edema) were less frequent for patients receiving NC combination therapy than N monotherapy. These analyses support the use of calcium antagonist and angiotensin receptor blocker combination therapy in patients with both mild and moderate hypertension, for whom effective BP normalization and good drug tolerance would greatly reduce the risk of cardiovascular events.


Subject(s)
Antihypertensive Agents/administration & dosage , Benzimidazoles/administration & dosage , Biphenyl Compounds/administration & dosage , Blood Pressure/drug effects , Calcium Channel Blockers/administration & dosage , Hypertension/drug therapy , Nifedipine/administration & dosage , Tetrazoles/administration & dosage , Adult , Aged , Blood Pressure/physiology , Double-Blind Method , Drug Therapy, Combination , Female , Humans , Hypertension/diagnosis , Hypertension/physiopathology , Internationality , Male , Middle Aged
14.
J Toxicol Environ Health A ; 78(20): 1299-309, 2015.
Article in English | MEDLINE | ID: mdl-26514876

ABSTRACT

Red ginseng (RG) is one of the top selling herbal medicines in Korea, but is not recommended in hypertensive patients. In this study, the pharmacokinetic (PK) interaction between RG and losartan, an antihypertensive drug, was examined. RG was orally administered for 2 wk to male Sprague-Dawley (S-D) rats at either control (0), 0.5, 1, or 2 g/kg/d for 2 wk. After the last administration of RG and 30 min later, all animals were treated with 10 mg/kg losartan by oral route. In addition, some S-D rats were administered RG orally for 21 d at 2 g/kg followed by losartan intravenously (iv) at 10 mg/kg/d. Post losartan administration, plasma samples were collected at 5, 15, and 30 min and 1, 1.5, 2, 3, 6, 12, and 24 h. Plasma concentrations of losartan and E-3174, the active metabolite of losartan, were analyzed by a high-pressure liquid chromatography-tandem mass spectrometer system (LC-MS/MS). Oral losartan administration showed dose-dependent pharmacokinetics (PK) increase with time to maximum plasma, but this was not significant between different groups. There was no significant change in tmax with E-3174 PK. With iv losartan, pharmacokinetics showed elevation of area under the plasma concentration-time curve from time zero extrapolated to infinitity. There was not a significant change in AUCinf with E-3174 PK. Therefore, RG appeared to interfere with biotransformation of losartan, as RG exerted no marked effect on E-3174 PK in S-D rats. Data demonstrated that oral or iv treatment with losartan in rats pretreated with RG for 2 wk showed that losartan PK was affected but E-3174 PK remained unchanged among different dose groups. These results suggested that RG induces negligible influence on losartan and E-3174 PK in rats.


Subject(s)
Antihypertensive Agents/pharmacokinetics , Imidazoles/pharmacokinetics , Losartan/pharmacokinetics , Panax/chemistry , Tetrazoles/pharmacokinetics , Administration, Intravenous , Administration, Oral , Animals , Antihypertensive Agents/administration & dosage , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Imidazoles/administration & dosage , Losartan/administration & dosage , Male , Rats , Rats, Sprague-Dawley , Tandem Mass Spectrometry , Tetrazoles/administration & dosage
15.
Intern Med ; 54(19): 2467-70, 2015.
Article in English | MEDLINE | ID: mdl-26424305

ABSTRACT

A 28-year-old man was referred to our hospital for the treatment of congestive heart failure and severe hypertension. The patient was diagnosed with malignant phase hypertension based on the presence of marked hypertension with left ventricular hypertrophy, exudate retinopathy, and renal failure. Intensive therapy for hypertension and heart failure with a combination of antihypertensive drugs including nitroglycerin, nifedipine, eplerenone and candesartan successfully lowered his blood pressure and further improved the renal function. Eplerenone could be one of the choices of antihypertensive drugs in combination therapy in patients with malignant phase hypertension with progressive heart and renal failure.


Subject(s)
Heart Failure/drug therapy , Hypertension, Malignant/drug therapy , Obesity/complications , Renal Insufficiency/drug therapy , Adrenergic beta-Antagonists/administration & dosage , Adult , Antihypertensive Agents/administration & dosage , Benzimidazoles/administration & dosage , Biphenyl Compounds , Calcium Channel Blockers/administration & dosage , Creatinine/blood , Drug Therapy, Combination , Eplerenone , Heart Failure/complications , Heart Failure/physiopathology , Humans , Hypertension, Malignant/pathology , Male , Nifedipine/administration & dosage , Nitroglycerin/administration & dosage , Obesity/blood , Obesity/physiopathology , Renal Insufficiency/blood , Renal Insufficiency/prevention & control , Spironolactone/administration & dosage , Spironolactone/analogs & derivatives , Tetrazoles/administration & dosage , Treatment Outcome , Vasodilator Agents/administration & dosage
16.
Pharmacology ; 96(5-6): 210-6, 2015.
Article in English | MEDLINE | ID: mdl-26329263

ABSTRACT

Cilostazol and L-carnitine have been used as a first-line drug and supplement, respectively, in patients with peripheral arterial disease with intermittent claudication. In this study, the effect of the combination of cilostazol and L-carnitine has been investigated in rats with unilateral hindlimb ischemia. For 28 days, cilostazol and L-carnitine were administrated separately or as a combination. The distance walked before gait disturbance developed was measured using a treadmill for 5 days a week. The capillary density of the ischemic hindlimb was evaluated by immunohistochemical staining at days 7, 14, 21, and 28. Angiogenic gene expression was measured by real-time RT-PCR at days 7 and 28. The greatest increase in the distance was observed in the combination therapy group when compared to the other groups. The capillary density in the adductor muscles of rats treated with cilostazol alone and combination therapy increased at day 28. Angiopoietin-2/Angiopoietin-1 expression ratios were higher, suggesting the promotion of angiogenesis, with cilostazol alone and combination therapy at day 7. This is the first study to show functional improvement of the hind limb following combination therapy with cilostazol and L-carnitine in experimental animals. This study also revealed that cilostazol promotes angiogenesis, and L-carnitine additively contributes to functional improvement via a non-angiogenic mechanism.


Subject(s)
Carnitine/therapeutic use , Peripheral Arterial Disease/drug therapy , Tetrazoles/therapeutic use , Vasodilation/drug effects , Walking , Angiogenic Proteins/genetics , Angiogenic Proteins/metabolism , Animals , Carnitine/administration & dosage , Cilostazol , Disease Models, Animal , Drug Therapy, Combination , Exercise Test/drug effects , Hindlimb/blood supply , Ischemia/drug therapy , Ischemia/physiopathology , Male , Muscle, Skeletal/blood supply , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Peripheral Arterial Disease/physiopathology , Rats, Sprague-Dawley , Tetrazoles/administration & dosage
18.
J Pharmacol Sci ; 127(1): 62-8, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25704020

ABSTRACT

This study was undertaken to evaluate the differences in chronotherapeutic effects of angiotensin-II receptor blockers, valsartan and olmesartan in hypertensive patients with non-dipper blood pressure (BP) pattern during valsartan at morning. Ninety four patients were enrolled, and 40 patients were judged to be non-dippers. In these patients, same dose of valsartan was changed to evening (Val-E, n = 12), or olmesartan (equivalent dose of valsartan) was given at morning (Olm-M, n = 13) or evening (Olm-E, n = 15) for 4 months. BP decreased during sleep and increased during waking hours in Val-E group. In Olm-M and Olm-E groups, BP decreased during sleep and waking hours. Percent reduction in BP at night-time compared to BP at waking hours significantly increased after changing the dose regimen in each group. Serum creatinine decreased and estimated glomerular filtration rate (eGFR) elevated in Olm-M and Olm-E, but not Val-E groups. Positive correlation between systolic BP (SBP) during sleep and serum creatinine, and negative correlation between SBP during sleep and eGFR were detected. These data suggest that dipper BP pattern could be obtained by chronotherapeutic approach using valsartan and olmesartan in non-dipper patients with valsartan at morning. Morning and evening olmesartan, but not evening valsartan improved renal function in these patients.


Subject(s)
Antihypertensive Agents/therapeutic use , Drug Chronotherapy , Hypertension/drug therapy , Imidazoles/therapeutic use , Tetrazoles/therapeutic use , Valsartan/therapeutic use , Aged , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Creatinine/blood , Female , Glomerular Filtration Rate/drug effects , Humans , Hypertension/blood , Imidazoles/administration & dosage , Imidazoles/pharmacology , Male , Middle Aged , Tetrazoles/administration & dosage , Tetrazoles/pharmacology , Valsartan/administration & dosage , Valsartan/pharmacology
19.
World Neurosurg ; 84(1): 28-35, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25701766

ABSTRACT

Subarachnoid hemorrhage (SAH) remains a condition with suboptimal functional outcomes, especially in the young population. Pharmacotherapy has an accepted role in several aspects of the disease and an emerging role in several others. No preventive pharmacologic interventions for SAH currently exist. Antiplatelet medications as well as anticoagulation have been used to prevent thromboembolic events after endovascular coiling. However, the main focus of pharmacologic treatment of SAH is the prevention of delayed cerebral ischemia (DCI). Currently the only evidence-based medical intervention is nimodipine. Other calcium channel blockers have been evaluated without convincing efficacy. Anti-inflammatory drugs such as statins have demonstrated early potential; however, they failed to provide significant evidence for the use in preventing DCI. Similar findings have been reported for magnesium, which showed potential in experimental studies and a phase 2 trial. Clazosentane, a potent endothelin receptor antagonist, did not translate to improve functional outcomes. Various other neuroprotective agents have been used to prevent DCI; however, the results have been, at best inconclusive. The prevention of DCI and improvement in functional outcome remain the goals of pharmacotherapy after the culprit lesion has been treated in aneurysmal SAH. Therefore, further research to elucidate the exact mechanisms by which DCI is propagated is clearly needed. In this article, we review the current pharmacologic approaches that have been evaluated in SAH and highlight the areas in which further research is needed.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Anticoagulants/therapeutic use , Brain Ischemia/prevention & control , Calcium Channel Blockers/therapeutic use , Neuroprotective Agents/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Subarachnoid Hemorrhage/drug therapy , Animals , Apoptosis , Brain Ischemia/etiology , Clinical Trials as Topic , Dexamethasone/administration & dosage , Dioxanes/administration & dosage , Dioxanes/pharmacology , Disease Models, Animal , Drugs, Chinese Herbal/administration & dosage , Estrogens/administration & dosage , Estrogens/adverse effects , Evidence-Based Medicine , Free Radical Scavengers/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Magnesium Sulfate/therapeutic use , Nimodipine/therapeutic use , Pregnatrienes/administration & dosage , Progesterone/administration & dosage , Progesterone/adverse effects , Pyridines/administration & dosage , Pyridines/pharmacology , Pyrimidines/administration & dosage , Pyrimidines/pharmacology , Receptor, Endothelin A/drug effects , Subarachnoid Hemorrhage/complications , Sulfonamides/administration & dosage , Sulfonamides/pharmacology , Tetrazoles/administration & dosage , Tetrazoles/pharmacology
20.
Antimicrob Agents Chemother ; 59(4): 1992-7, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25605358

ABSTRACT

Current therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potent in vitro antifungal activity against dermatophytes, with MIC values in the range of ≤0.016 to 0.5 µg/ml. In pharmacokinetic studies supporting testing in a guinea pig model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potential in vivo efficacy with once-daily and possibly once-weekly dosing. Subsequently, in a guinea pig dermatophytosis model utilizing Trichophyton mentagrophytes and at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction (P < 0.001) and improvement in clinical scores (P < 0.001). The efficacy profile of VT-1161 was equivalent to those for doses and regimens of itraconazole and terbinafine except that VT-1161 was superior to itraconazole when each drug was dosed once weekly (P < 0.05). VT-1161 was distributed into skin and hair, with plasma and tissue concentrations in all treatment and regimen groups ranging from 0.8 to 40 µg/ml (or µg/g), at or above the MIC against the isolate used in the model (0.5 µg/ml). These data strongly support the clinical development of VT-1161 for the oral treatment of onychomycosis using either once-daily or once-weekly dosing regimens.


Subject(s)
Antifungal Agents/administration & dosage , Antifungal Agents/therapeutic use , Pyridines/administration & dosage , Pyridines/therapeutic use , Tetrazoles/administration & dosage , Tetrazoles/therapeutic use , Tinea/drug therapy , Animals , Antifungal Agents/pharmacokinetics , Dose-Response Relationship, Drug , Guinea Pigs , Itraconazole/administration & dosage , Itraconazole/therapeutic use , Male , Microbial Sensitivity Tests , Pyridines/pharmacokinetics , Skin/pathology , Tetrazoles/pharmacokinetics , Tinea/microbiology , Tinea/pathology , Tissue Distribution , Trichophyton/drug effects
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