Outcome evaluation combination therapy

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... 

What is the evidence that hypothermia plus other potential neuroprotective therapies actually does improve outcome compared with individual neuroprotective agents Surprisingly, there are few preclinical and no human studies that have examined this issue. The main reason for this lack of study likely stems from the added complexity necessary for a combined treatment study, and the desire by most researchers to identify individual agents with neuroprotective properties first before proceeding to evaluate combination treatments. However, a handful of experimental treatment studies have been performed using hypothermia in conjunction with other neuroprotective agents, with surprisingly mixed results. 

Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Haneteld M, Jones NP, Komajda M, McMurray JJV. For the RECORD study team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD) a multicentre, randomised, open-label trial. Lancet 2009 373 2125-35. 

Finally, it is known that HA as glycosaminoglycan and chondroitin sulphate (CS) protect the urothelium but a damage to the urothelium may increase bacterial adherence and cause infection risk. For this a meta-analysis was carried out in order to evaluate the effect of intravesical HA and HA and CS (HA-CS) combination therapy in recurrent bacterial cystitis in adult women. A systematic literature search was performed. Primary outcomes were urinary tract infection (UTI) rate per patient-year, and UTI recurrence time (days). Secondary outcomes were 3-day voids and pelvic pain and urgency/frequency (PUF) symptom scale total score [35. ... 

Ezetimibe interferes with the absorption of cholesterol from the brush border of the intestine, a novel mechanism that makes it a good choice for adjunctive therapy. It is approved as both monotherapy and for use with a statin. The dose is 10 mg once daily, given with or without food. When used alone, it results in an approximate 18% reduction in LDL cholesterol. When added to a statin, ezetimibe lowers LDL by about an additional 12% to 20%. A combination product (Vytorin) containing ezetimibe 10 mg and simvastatin 10, 20, 40, or 80 mg is available. Ezetimibe is well tolerated approximately 4% of patients experience GI upset. Because cardiovascular outcomes with ezetimibe have not been evaluated, it should be reserved for patients unable to tolerate statin therapy or those who do not achieve satisfactory lipid lowering with a statin alone. 

The median follow-up was 23 mo for the 1073 evaluable patients. Patients that received hyperfractionated or accelerated radiation therapy with boost had increased locoregional control (p = 0.045 and p = 0.05, respectively) and a trend toward improved disease-free survival (DFS) (p = 0.067 and p = 0.054, respectively) in comparison to conventional radiation therapy. However, there was no improvement in overall survival(s). Patients given accelerated split-course fractionation had similar outcomes to those who had received conventional radiotherapy. Hyperfractionated radiation therapy is the method of choice for combined chemoradiotherapy in current investigative approaches for head and neck cancer. 

Outcome measurements used in the evaluation of the outcome of treatment of RA with sulfasalazine, parenteral gold salts, D-penicillamine, hydroxychloroquine, prednisolone, MTX, cyclophosphamide (CyC), and azathioprine in single drug therapy cannot be compared with endpoints used in SBC-5-lMNs and biological-DMARDs combined with MTX. 

In the Heart Outcomes Prevention Evaluation 2 (HOPE-2) study, 5522 patients aged 55 or older with vascular disease or diabetes were randomized to treatment with either placebo or a combination 2, 5 mg of folic acid, 50 mg vitamin B6, and I mg vitamin B 2, for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke. Mean plasma homocysteine levels decreased by 2.4 jimol/L in the treatment group and increased by 0.8 jimol/L in the placebo group. The primary outcome occurred in 18.8% of patients assigned to active therapy and in 19.8% of those assigned to placebo (relative risk = 0.95 95% Cl = 0.84-1.07 P = 0.41) (68). 

One factor to keep in mind when evaluating disulfiram is that its effects may be enhanced considerably if its u.se is combined with a behavioral program that in part consists of supervised administration of the disulfiram (e.g., by the patient s spouse) to the patient (Hughes Cook, 1997). This apparently addresses a major practical problem with using disulfiram clinically It typically requires daily administration of the prescribed dose, and patients tend to show poor compliance with such a regimen. Disulfiram implants have been tried as another w ay to solve the compliance problem, but their effectiveness has not been shown clearly, and the bioavailability of the implanted disulfiram has not been demonstrated in clinical trials. Additional well-controlled studies of supervised disulfiram therapy would allow us to specife the conditions under which its administration is most likely to enhance outcomes. 

More recent data suggest that all patients with CAD, not just ACS or heart failure patients, benefit from an ACE inhibitor. In the Heart Outcome Prevention Evaluation (HOPE) trial, ramipril significantly reduced the risk of death, MI, or stroke in high-risk patients aged 55 years or older with chronic CAD or with diabetes and one cardiovascular risk factor. The more recent European trial On Reduction Of Cardiac Events With Perindopril In Stable Coronary Artery Disease (EUROPA) extended the benefit of chronic therapy with ACE inhibitors to patients with stable CAD at lower risk of cardiovascular events compared with patients from the HOPE trial. In the EUROPA trial, patients randomized to perindopril experienced a lower risk of the combined end point of cardiovascular death, MI, or cardiac arrest compared with patients randomized to placebo. Therefore, based on the extensive benefit of ACE inhibitors in patients with CAD, their routine use should be considered in all patients following an ACS in the absence of a contraindication. 

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