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PubMed1983

Chemotherapeutic study on Yoshida sarcoma ascites cells implanted into the glandular stomach of rats. Monotherapy with 5-fluorouracil, methyl-CCNU, mitomycin C, adriamycin, and cytosine arabinoside, and combination therapy with respective two-drug combinations.

The chemotherapeutic activity of five cytostatic drugs was investigated experimentally in monotherapy and in two-drug combinations, using Yoshida sarcoma cells implanted into the wall of the glandular stomach of Sprague-Dawley rats. In monotherapy, the antibiotic agent mitomycin C and the nitrosourea methyl-CCNU exhibited the highest cytotoxic activity in this tumor model. In combination therapy, the combination of these two drugs was superior to all the other therapeutic schemes tested. In general, the results demonstrate a marked superiority of combination therapy in comparison with monotherapy.

Animals↗
PubMed2005

Reducing residual risk for patients on statin therapy: the potential role of combination therapy.

Cholesterol-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, has been established as an effective method of reducing death and myocardial infarction among patients with coronary artery disease (CAD). However, a significant number of patients receiving statin therapy continue to have high residual risk. An important clinical challenge exists in reducing residual CAD risk with optimal therapies without increasing adverse effects. Combination therapy appears most appropriate for patients with a high rate of events of residual risk despite optimal statin therapy. This article discusses the role of combination therapy in managing CAD and in achieving optional targets in high-risk patient populations.

Atorvastatin↗
PubMed1993

Intensive insulin therapy in insulin dependent diabetes and combination therapy.

Intensive insulin therapy (IIT) and combination therapy using sulfonylurea and insulin are two insulin regimens being used more frequently to improve glycemic control. For those patients with insulin-dependent diabetes, IIT or multiple daily injection therapy mimics normal pancreatic function by its timing of insulin delivery. The improvement in glycemic control carries with it the risk of a two- to threefold increase in episodes of hypoglycemia. For those with non-insulin-dependent diabetes, combination therapy attempts to provide a bridge between maximal dose oral hypoglycemic agents and aggressive insulin therapy. Although this therapy remains controversial, it has proved useful in select patient groups. This article discusses the rationale for IIT, and its implementation. Variables that affect IIT are discussed. The combination therapy section provides guidelines for patient selection and insulin protocols for evening insulin administration. The health care provider is familiarized with these alternative therapies and their successful applications.

Blood Glucose↗
PubMed1988

Management of severe intra-abdominal sepsis: single agent antibiotic therapy with cefotetan versus combination therapy with ampicillin, gentamicin and metronidazole.

In a prospective, randomized trial involving 100 patients with severe intra-abdominal sepsis, the value of single agent antibiotic therapy with cefotetan was compared with that of combination therapy of ampicillin, gentamicin and metronidazole (AGM). All patients underwent exploratory laparotomy. The mortality rate was 3 per cent, all deaths occurring within 48 h of operation. Two-thirds of patients were considered severely ill on admission, and one-third were moderately ill. Six patients had positive blood cultures on entry into the study. The mean age was 31 years and concurrent disease was present in 14 per cent of the patients. A satisfactory response was achieved in 82 per cent of patients receiving cefotetan and in 65 per cent of those receiving AGM, whereas the response was unsatisfactory in 18 per cent of cefotetan patients and 35 per cent of those receiving AGM (P = 0.075 n.s.). Significant changes in laboratory values during the study occurred in 51 per cent of patients, and 7 per cent required vitamin K administration for hypoprothrombinaemia. The results of this study suggest that antibiotic therapy with single agent cefotetan is as safe and effective as a combination of ampicillin, gentamicin and metronidazole in patients with severe intra-abdominal sepsis requiring operative management.

Abdomen↗
PubMed1997

Safety and efficacy of hydroxychloroquine as maintenance therapy for rheumatoid arthritis after combination therapy with methotrexate and hydroxychloroquine.

OBJECTIVE: To evaluate the ability of hydroxychloroquine sulfate (HCQ) to extend the response to combination therapy with HCQ and methotrexate (MTX) and the safety of longterm HCQ maintenance therapy in patients with active rheumatoid arthritis (RA). METHODS: Two-part study consisting of an open label segment evaluating combination HCQ/MTX therapy followed by a double blind segment evaluating maintenance therapy for a total of 60 weeks. First, all patients were treated with HCQ 400 mg/day and MTX 7.5 to 15 mg/week for 24 weeks. Then, responders were randomized into 3 groups: (1) HCQ with MTX as needed for disease flare (n = 40), (2) HCQ 400 mg/day (n = 41), or (3) placebo with MTX as needed for disease flare (n = 40), each for 36 weeks. RESULTS: Clinical disease and laboratory variables improved significantly during initial combination therapy with HCQ and MTX. After MTX withdrawal, HCQ-containing maintenance regimens delayed the onset of disease flare (p = 0.023). There were no unexpected adverse events at any time or between-group differences in the distribution of adverse events during the double blind segment. CONCLUSION: Combination of HCQ and MTX appeared to be effective and well tolerated for 24 weeks. After withdrawal of MTX, HCQ extended the response seen with combination therapy and was well tolerated for 36 weeks. Initial therapy with HCQ and MTX, followed by maintenance HCQ, may be a useful alternative for the treatment of RA.

Aged↗
PubMed2005

The Avoiding Cardiovascular events through COMbination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial: a comparison of first-line combination therapies.

Although multidrug therapy is required in order to achieve good blood pressure control in many hypertensives, there are no studies directly comparing fixed-dose combinations as initial therapy. The Avoiding Cardiovascular events through COMbination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial compares regimens of benazepril plus amlodipine versus benazepril plus hydrochlorothiazide, force-titrated to 40/10 and 40/25mg, respectively. A total of 12,600 high-risk hypertensives have been randomised and will be followed for 3 - 5years, during which cardiovascular events will be monitored. The investigators hypothesise that the benazepril plus amlodipine regimen will decrease cardiovascular events by 15% compared with benazepril plus hydrochlorothiazide. Recruitment began in 2003, and the trial is expected to end in 2008. The ACCOMPLISH trial shares important limitations with many other recent trials that will make it difficult to apply the results in clinical practice. These include the focus on high-risk hypertensive patients, in whom significant reductions in relative risk will translate into meaningful reductions in absolute risk: in lower-risk hypertensives with a low absolute risk, similar relative risk reductions may not be of great impact on the population disease burden. In ACCOMPLISH, as in most industry-sponsored clinical trials, the main goal appears to be market-driven: doses of drugs tested are not those available for clinical practice. The question asked, whether the combination of benazepril with either diuretic or dihydropyridine calcium channel blocker is more efficacious, is not a clinically compelling one. Finally, the univariate subgroup analyses proposed are unlikely to lead to an understanding of whether either combination has specific advantages for patients encountered clinically, most of whom have multiple risk factors. Thus, it appears that ACCOMPLISH, as with many recent pharmacological trials, will not greatly impact the treatment of hypertension.

Amlodipine↗
PubMed2005

[Efficacy and safety of combination therapy with simvastatin and fenofibrate for combined hyperlipidemia].

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of combination therapy with simvastatin and fenofibrate in patients with combined hyperlipidemia. METHODS: A total of 221 patients with combined hyperlipidemia were randomly assigned to receive 10 mg simvastatin (n = 72) or 200 mg fenofibrate (n = 68), or a combination of 10 mg simvastatin + 200 mg fenofibrate (n = 81) for 6 months. Lipid profiles, physical and laboratory investigations for adverse effects were assessed. RESULTS: (1) Combination treatment were more effective in normalizing lipid profile than any monotherapy. Serum TC, LDL-C, and TG were reduced by 30%, 37% and 56% respectively, whilst HDL-C significantly increased by 24% (all P < 0.01). The improvement in TG and HDL-C achieved by combination treatment was superior to fenofibrate or simvastatin alone. (2) The success rate of TC, LDL-C and TG control in the combination therapy group were 51%, 55% and 61% respectively, with an overall success rate (all three together) of 45%, which was superior to either drug given as monotherapy. (3) All treatments were well tolerated with no increase in adverse events for combination therapy versus monotherapy. CONCLUSION: The results of this study demonstrated that combination therapy with fenofibrate (200 mg/day) and low-dose simvastatin (10 mg/day) is more effective than monotherapy in patients with combined hyperlipidemia, and is generally safe and well tolerated.

Drug Therapy, Combination↗
PubMed2001

Combination therapy for sarcoidosis.

Combination therapy has proved useful in infectious, rheumatologic, and oncologic diseases. The role of combination therapy in sarcoidosis is less defined. A stepwise approach to therapy in sarcoidosis treatment includes multiple agents, such as topical and systemic corticosteroids. The introduction of cytotoxic agents has led to the combination of these drugs with lowered doses of corticosteroids. Recently, the combination of cytotoxic and immune modifiers has been used for some cases of refractory sarcoidosis. The rationale use of combination therapy may enhance efficacy with reduced toxicity.

Adrenal Cortex Hormones↗
PubMed2004

Statins as the cornerstone of drug therapy for dyslipidemia: monotherapy and combination therapy options.

Low-density lipoprotein (LDL) cholesterol reduction with statin treatment remains the cornerstone of lipid-lowering therapy to reduce risk of coronary heart disease. Combination therapy with a statin poses advantages in certain settings and may allow use of lower doses of multiple drugs rather than maximum doses of a single drug. Bile-acid sequestrants or the cholesterol-absorption inhibitor ezetimibe can be added to a statin to achieve greater LDL cholesterol reductions. Niacin or fenofibrate can be added to a statin for treatment of mixed dyslipidemia. Differences in statin efficacy in reducing LDL cholesterol and meeting recommended LDL cholesterol targets as well as differences among these agents in beneficial effects on other lipid parameters can affect whether and how these agents are prescribed in monotherapy and combination therapy.

Alanine Transaminase↗
PubMed2003

Questionnaire to peritoneal dialysis patients undergoing combined therapy (peritoneal dialysis and hemodialysis).

Combined therapy [peritoneal dialysis (PD) and hemodialysis (HD)] has been used for ultrafiltration failure and inadequacy of dialysis dose in PD patients. To support the transition to, and continuation of, combined therapy, we investigated patient feelings about combined therapy. We performed a questionnaire survey of 23 combined-therapy patients (mean age: 48.9 years; mean PD duration: 67.9 months; mean combined therapy duration: 21.2 months). The questionnaire asked about feelings before and after combined therapy, physical improvements after combined therapy, and the patient's hopes about the method of dialysis therapy in the future. One patient did not answer, and one questionnaire was removed from the analysis owing to invalid responses. Before combined therapy, 15 patients (71.4%) had negative feelings toward combined therapy. After combined therapy, more than half of the patients experienced improvement in edema, general condition, weight control, complexion, and fatigue. Seventeen patients (81.0%) were satisfied with combined therapy, but 15 patients (71.4%) were uncomfortable with HD. For the future, 15 patients (71.4%) wanted to continue combined therapy, and 5 patients (23.8%) hoped to return to PD only. Patients accepted combined therapy because of the physical improvements, but were uncomfortable with HD because of hospital visits and pain from puncture. Before introducing PD, we need to provide accurate information about PD, combined therapy, HD, and the process of dialysis therapy.

Attitude↗
PubMedDate not supplied

Early developments in combination therapy.

The concept of combination therapy implies the concurrent use of two or more slow-acting antirheumatic drugs to treat rheumatoid arthritis. This review places such combination therapy into an historical context and evaluates studies carried out before 1990. There were no published studies before 1980 of combination therapy, and between 1980 and 1990 there were 11 published studies. Three were conventional randomised controlled trials, three were non-randomised studies of parallel group design, four were observational open studies, and one was a retrospective review. Altogether 486 patients were studied with the numbers of cases in each study varying between 12 and 101. The main combinations used were penicillamine + hydroxychloroquine or chloroquine, gold + hydroxychloroquine, and sulphasalzine + penicillamine. Six studies concluded that combination therapy helped patients, three suggested possible benefits, and two gave essentially negative findings. These two negative studies were randomised controlled trials. Most studies indicated an increase in adverse events with combination therapy. The average erythrocyte sedimentation rate on combination therapy fell by 21.4%. A majority of patients remained on the therapy for 6-12 months. The balance of evidence in 1990 suggested that combination therapy had a modest advantage. However, the trials were too small to detect its true value, and the combinations used were not ideal. In particular, combining gold or penicillamine with other drugs appeared to give too much toxicity. The future development of the field would depend on identifying more effective combinations of drugs and undertaking larger and better-designed trials.

Antirheumatic Agents↗
PubMed1996

Newer approaches to antihypertensive therapy. Use of fixed-dose combination therapy.

Despite the availability of many newer antihypertensive agents, hypertensive patients remain at higher risk of premature death than the general population. This persistence of morbidity and mortality may be accounted for by the frequent failure to achieve adequate blood pressure reduction despite an extensive array of available antihypertensive agents. Such considerations have led to reassessment of the potential role of fixed-dose combination agents in the antihypertensive armamentarium. The rationale for combination therapy relates to the concept that antihypertensive efficacy may be enhanced when 2 classes of agents are combined. In addition, combination therapy enhances tolerability-1 drug of a fixed combination can antagonize some of the adverse effects of the second drug. Fixed-dose combination therapy simplifies the treatment regimen, preventing treatment failures that might result from missed doses. An additional novel concept is the possibility of enhancing salutary effects on target organs, including regressing left ventricular hypertension and retarding progression of renal disease, by combination therapy over and above the effects expected from the fall in arterial pressure alone. The recent approval by the Food and Drug Administration of 2 fixed-dose angiotensin-converting enzyme inhibitor/calcium antagonist combinations has focused attention on and prompted reexamination of this issue.

Antihypertensive Agents↗
PubMed2002

[Drug therapy of benign prostatic hyperplasia. Is combination therapy with 5 alpha-reductase inhibitors and alpha-receptor blockers effective?].

5 alpha-reductase inhibitors and alpha 1-receptor blockers are the two main drug therapies used in the management of symptomatic benign prostatic hyperplasia. As alpha-reductase inhibitors and alpha 1-receptor blockers act through different mechanisms, a combination of the two agents might be promising. The potential benefits of combination therapy with selective alpha 1-receptor blockers and finasteride, a 5 alpha-reductase inhibitor, are currently being evaluated in several placebo-controlled prospective multicenter studies (VA Study, ALFIN Study, PREDICT Study, and MTOPS Study). The data from these studies available so far demonstrate a statistically significant benefit for the study groups receiving alpha 1-receptor blockers and combination therapy vs placebo and finasteride monotherapy in terms of symptom scores and peak urine flow rates. However, none of the studies yielded a statistically significant advantage of combination therapy over treatment with alpha 1-receptor blockers. These results should be interpreted with reference to the prostatic volume, which in the studies mentioned above was relatively low. From the results of all these studies, it can be concluded that in symptomatic patients with prostate volumes of up to 40-45 ml a combination of 5 alpha-reductase inhibitors with alpha 1-receptor blockers does not appear to provide any benefit. Yet, it can be assumed that in symptomatic patients with prostate volumes of more than 60 ml combination therapy may indeed prove more effective.

5-alpha Reductase Inhibitors↗
PubMed2003

[Antimicrobial combination therapy].

Anti-microbial combination therapy is a very frequently used therapeutic approach although clinical data from prospective randomized trials thus fulfilling the criteria of evidence based medicine are very rare. Rationales for the use of combination therapy are thus empirical treatment of polymicrobial infections, infections in critical ill or in immuno-compromised patients, prevention of the emerge of antibiotic resistances, utilization of a potential synergism of antibiotics directed against a certain bacterial strain, or simply despair. Prospective studies have demonstrated a superiority of combination therapy over single drug regimen in enterococcal endocarditis, and infections with gram negative rods including pseudomonas sp., but in the latter condition only if the patient is severely immuno-compromised. There is clinical indication that combination therapy may be beneficial in infections with staphylococci sp., however, well designed studies supporting this experience are largely absent. Nonetheless, antimicrobial combination therapy also harbors some risks for patients which can be referred to potential antagonism between antibiotics, accumulation of side effects, or stimulation of resistance pathways in bacteria by one drug leading to destabilization of the other one. Thus, the insightful use of combination therapy is warranted and well designed, prospective studies are urgently needed to evaluate the true benefit of combination therapy for the treatment of different infections and specific micro-organisms.

Anti-Bacterial Agents↗
PubMed2004

Lefunomide in combination therapy.

In most studies of disease modifying antirheumatic drug therapy, in combination with either leflunomide or biological agents, patients are given an additional agent after they have failed treatment with methotrexate (MTX). This review of clinical studies shows that leflunomide is clinically efficacious and well tolerated when added to either sulfasalazine or MTX, as both an initial and ongoing treatment for rheumatoid arthritis (RA). Experience in combining leflunomide with biological agents is limited to a small number of open-label studies with infliximab. According to the opinion obtained at an International Expert Panel Meeting held in Paris in May 2003, leflunomide can be used in combination therapy: 61% of the Expert Panel would use leflunomide with MTX, 71% with sulfasalazine, 43% with infliximab, 33% with adalimumab, 19% with etanercept, and 38% with anakinra. The Expert Panel stated that the combination of leflunomide and infliximab warrants a prospective, randomized, controlled trial in patients with incomplete clinical responses to leflunomide monotherapy, provided leflunomide is started first, without a loading dose, and infliximab is added after good tolerability to leflunomide has been established. The Expert Panel concluded that combination therapy with leflunomide has a place in the treatment of RA. Caution is advised, however, when using combination treatments and, therefore, the patient's safety should be carefully monitored.

Antibodies, Monoclonal↗
PubMedDate not supplied

A new approach to antithrombotic therapy--evaluation of combined therapy of thromboxane synthetase inhibitor and very low dose of aspirin.

The effect of a selective thromboxane (TX) synthetase inhibitor (OKY-046), alone and in combination with a very low dose of aspirin, on the platelet function was studied in healthy and diseased subjects. A single dose of 100 mg OKY-046 was orally administered to patients with ischemic cerebrovascular disease (CVD) and healthy volunteers. TXB2 generation and platelet aggregation were measured before and at 1, 4, 6 and 8hr after dosing. In addition, after the administration of a very low dose of aspirin (0.1-0.25 mg/kg/day) for at least one month, a single dose of OKY-046 was given to CVD patients. TXB2 generation and platelet aggregation were measured in the same manner as OKY-046 alone. The effect of OKY-046 on platelet aggregation induced by arachidonic acid (AA) was different in each subject whereas platelet TXB2 generation was almost completely inhibited in all of the patients and healthy volunteers. OKY-046 had a slight inhibitory effect on collagen induced aggregation. A combination of OKY-046 with a very low dose of aspirin, on the other hand, produced additional inhibition of the platelet aggregation induced by both AA and collagen. The present results suggest that the accumulation and metabolism of cyclooxygenase products that accumulate when TX synthetase is blocked, differ in each subject, additional inhibition is caused by the combined use of TX synthetase inhibitor and a very low dose of aspirin because the very low dose of aspirin partially reduces the proaggregatory cyclooxygenase products that accumulate when TX synthetase is blocked.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylates↗
PubMed1992

[Familial hypercholesterolemia--intensive diet therapy combined with drug therapy].

The aim of the investigation was twofold: to study the effect of lovastatin, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, alone and in combination with other lipid lowering drugs in an open 48 week single centre study, and to study if lipid lowering drugs influence adherence to diet in adult patients with familial hypercholesterolemia. Lovastatin monotherapy (80 mg daily) for 12 weeks reduced serum cholesterol, LDL-cholesterol and triglycerides levels by 36%, 44% and 24% respectively. HDL-cholesterol level was increased by 12%. The addition of 16 g cholestyramine daily further increased the reduction of total cholesterol and LDL-cholesterol levels by 17% and 24% respectively. Addition of 1 g probucol daily decreased total cholesterol, LDL-cholesterol and HDL-cholesterol levels by 9%, 5% and 27% respectively. Addition of omega-3-fatty acids (3.6 g daily) reduced total cholesterol, LDL-cholesterol and triglycerides levels by 10%, 12% and 20% respectively. Administration of potent lipid lowering agents did not influence adherence to a diet with a mean daily fat energy of 21% (CI: 20-22), cholesterol of 177 mg (CI: 157-196) and P/S ratio of 0.75 (CI: 0.66-0.84). A significant increase in liver enzymes was recorded in only one patient. One patient was withdrawn from the study because of myositis.

Adolescent↗