Combined therapies patient evaluation

Since ACEIs and ARBs have demonstrated efficacy in patients with diabetes, the possibility of using both agents in type 2 diabetics has been investigated. This short-term (12 to 24 weeks) study evaluated lisinopril (20 mg once daily) and candesartan (16 mg once daily) versus the combination in 199 patients. The reduction of urinary albumin creatinine ratios were greater with combination therapy (50%) than either lisinopril (39%) or candesartan (24%) alone. Blood pressure reduction, however, was also significantly greater in the combination therapy patients. Thus it is not clear if the combination produced an enhanced antiproteinuric effect or if the reduction in the albumin creatinine ratio could be attributable to the greater reduction in blood pressure. ... 

The second study was the European International Study of Infarct Survival (ISIS II) Trial (11). This study randomized patients suspected of having an AMI (there were no ECG inclusion criteria) to one of four arms placebo, aspirin only, streptokinase only, or streptokinase plus aspirin. Thus, this was the first large trial of combination therapy to evaluate the impact of treating both the fibrin and the platelet components of clot. Of 17,187 patients randomized, mortality at 30 days was lowered by 21% in those treated with streptokinase, from 13.2% in the placebo group to 10.4%, with a similar 19% reduction to 10.7% in those treated with aspirin alone. Those receiving both agents had a 39% reduction in mortality to 8.0% (p < 0.05 for all comparisons). These patients were enrolled up to 24 hours after symptom onset, and the median time to treatment was 5 hours. Heparin therapy was not included in the protocol regimen. 

More recently, the value of adding the combination of isosorbide dinitrate 40 mg and hydralazine 75 mg three times daily to therapy including ACE inhibitors, P-blockers, digoxin, and diuretics was evaluated in a prospective, randomized trial26 The study enrolled only African-American patients and demonstrated a significant reduction in mortality, as well as first hospitalization for HF. Quality-of-life scores were also improved over placebo. Combination therapy with hydralazine and isosorbide dinitrate is an appropriate substitute for angiotensin II antagonism... 

Fibrates are being combined with statins to expand their potential in the dyslipidemia market. A recent clinical study examined the effects of rosuvastatin (10) and fenofibrate as mono and combination therapy in hyperlipidemic diabetic patients [43]. In late 2006, large scale Phase III clinical trials of rosuvastatin in combination with a next-generation fibrate, ABT 335, were initiated for evaluation of safety and efficacy in patients with mixed dyslipidemia. 

Takeda et al. (64) performed a phase I/II study consisting of low-dose CDDP (6-10 mg/m2/d) and UFT (600 mg/d) combined with radiotherapy (50 Gy/25 fractions) as postoperative adjuvant therapy following curative resection for patients with nonsmallcell lung cancer (NSCLC). The combined therapy was well tolerated and resulted in a disease-free survival rate of 78% at 2 yr. Another study in a small number of patients with unresectable stage III nonsmall-cell lung cancer, UFT (400 mg/m2 on d 1-52) and CDDP (80 mg/m2 on d 8,29, and 50) were administered with radiation therapy (total dose of 60.8 Gy in 38 fractions on d 1-52). Among 17 evaluable patients, 94% (16 patients) achieved partial responses with median time to tumor progression of 30 wk, and the... 

E. Therapeutic response Oncaspar was evaluated as part of combination therapy in open-label studies of relapsed, previously L-asparaginase hypersensitive acute leukemia patients. The reinduction response rate was 50% (36% complete remissions and 14% partial remissions). 

Pioglitazone also causes fluid retention, possibly because of increased production of vascular endothelial growth factor (92). The safety profile of monotherapy and combined therapy with pioglitazone has been evaluated in 3500 patients over 2500 patient-years, and some data from post-marketing surveillance were included peripheral edema and hemodilution were common (93). 

Based on experimental and clinical data, cerebral hypothermia appears to be a potent therapeutic approach to treating brain trauma. However, recent results from the Multicenter National Brain Injury Study Hypothermia (NABIS H) clinical trial appear to be disappointing, and more refinement of the clinical application of hypothermia is required (73). Additional clinical trials are now required to evaluate systematically the beneficial effects of clinical hypothermia in different populations of brain-injured patients. In addition, experimental data regarding the beneficial effects of combination therapy are required to evaluate whether hypothermia plus pharmacotherapy may provide a better outcome. Forexample, mildpostischemichypothermia(33-39°C) combined with the antiinflammatory cytokine IL-10 has recently been reported to produce long-term protection of the C Al hippocampus after transient global ischemia (74). Hypothermia or IL-10 treatment alone did not protect chronically. In contrast, Kline etal. (75) showed that acute systemic administration of IL-10 suppressed the beneficial effects of... 

Anticonvulsant Evaluation (BALANCE) Study is now under way. It involves combination therapy with either lithium 400 mg/day plus valproate 500 mg/day or double those doses and then randomization to double-blind treatment with lithium plus valproate placebo, lithium plus valproate, or valproate plus lithium placebo. The study involves patients with bipolar I affective disorder who... 

Allopurinol and meglumine antimoniate (Glucantime) have been evaluated in a randomized controlled trial in 150 patients with cutaneous leishmaniasis (2). They received oral allopurinol (15 mg/kg/day) for 3 weeks or intramuscular meglumine antimoniate (30 mg/kg/day, corresponding to 8 mg/kg/day of pentavalent antimony, for 2 weeks), or combined therapy. There were a few adverse effects in those who used allopurinol nausea, heartburn (n = 3), and mild increases in transaminases (n = 2). These symptoms subsided on drug withdrawal. 

The effects of antihypertensive agents have been evaluated in patients taking ciclosporin. Collectively, dihydropyridine calcium channel blockers that do not affect ciclosporin blood concentrations substantially or at all (felodipine, isradipine, and nifedipine) are usually considered to be the drugs of choice. However, the risk of gingival hyperplasia with nifedipine, which ciclosporin also causes, should be borne in mind. Combination therapy with angiotensin-converting enzyme inhibitors or beta-blockers, or the use of other calcium channel blockers (verapamil or diltiazem) should also be considered, but careful monitoring of ciclosporin blood concentrations is recommended with the latter because they inhibit ciclosporin metabolism. 

Initial studies indicate that ARBs and ACE inhibitors produce similar hemodynamic effects and that combination therapy improves exercise capacity, ventricular function, quality of life, and neurohormones in heart failure patients. The ELITE II trial was the first to compare the effects of an ARB (losartan) with those of an ACE inhibitor (captopril) on all-cause mortality in patients with NYHA class II-IV heart failure. No significant difference in mortahty between the two groups was observed, although losartan was better tolerated than captopril. The Val-HeFT trial evaluated whether the addition of valsartan to standard background heart failure therapy (which included an ACE inhibitor in 93% and a /3-blocker in 35% of patients) improved survival. The addition of valsartan had no effect on all-cause mortality but produced a 13% reduction in morbidity and mortality (principally due to reductions in heart failure hospitalizations). Subgroup analysis showed that the benefits were greatest in... 

A recent pharmacoeconomic analysis to examine the clinical benefits and cost-effectiveness of newer treatments for chronic HCV infection evaluated the incremental cost-effectiveness of using peginterferon-a2b plus ribavirin compared to IFN-a2b plus ribavirin, and monotherapy regimens of both interferons. The incremental cost per quality-adjusted fife year (QALY) saved for combination therapy with peginterferon-a2b compared to standard therapy was 36,000 and 55,000 for men and women with HCV genotype 1, respectively. A QALY is defined as a patient s desire for a year of fife at... 

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