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PubMed2002

[Efficacy and safety of combination therapy with losartan and hydrochlorothiazide in elderly hypertension].

We examined the effect and safety of combination therapy with low-dose diuretics (hydrochlorothiazide: HCTZ) and angiotensin II receptor antagonist (losartan) in elderly cases of hypertension, using ambulatory blood pressure monitoring (ABPM). Elderly hypertensive patients (mean age 75 +/- 2 years) were treated with either losartan (25-50 mg/day) or HCTZ (12.5 mg/day) for at least 4 weeks, and then 24-hour blood pressure (BP) was measured by ABPM. Combination therapy with addition of other drug was initiated in 14 patients whose 24-hour systolic BP or daytime systolic BP was over 140 mmHg (160 mmHg for the patients of 80 years or older). After 4 weeks of the combination therapy, ABPM was repeated. Blood cell count and blood chemistry were also done before and after initiation of combination therapy. In the losartan-preceding group (n = 9), the combination therapy with HCTZ reduced 24-hour BP by 19.3 +/- 2.3/6.6 +/- 2.3 mmHg. Similarly, daytime and nighttime BP decreased by 21.4 +/- 4/8.4 +/- 2.8 mmHg and 15.2 +/- 4/4.2 +/- 2.4 mmHg, respectively. In the HCTZ-preceding group, the combination with losartan also decreased 24-hour BP by 12.2 +/- 4.8/3.4 +/- 1.4 mmHg. The decreases of daytime and nighttime BP were 13.8 +/- 6.6/4 +/- 1.1 mmHg and 10 +/- 4.7/3 +/- 2.4 mmHg, respectively. Heart rate did not change with combination therapy in the losartan-preceding group, while heart rate during daytime tended to decrease by addition of losartan in the HCTZ-preceding group (3.8 +/- 1.7/min). Serum electrolytes, uric acid, lipids, renal function and body weight did not change during the study period. Thus, combination therapy of losartan/hydrochlorothiazide seems useful in the treatment of elderly hypertension, showing additive BP lowering effect without metabolic adverse effects.

Aged↗
PubMed2004

Combination therapy of long-acting beta2-adrenoceptor agonists and corticosteroids for asthma.

Twice-daily combination therapy of inhaled corticosteroids and long-acting beta2-adrenoceptor agonists (LABA) is now established as a most effective treatment for moderate to severe asthma and is available in a combined single inhaler. The benefits of combination therapy include better day-to-day control and a reduction in exacerbations compared with monotherapy with inhaled corticosteroids at a lower dose. Total control of asthma, defined as no daytime or night-time symptoms, no use of rescue beta2-adrenoceptor agonists (beta2-agonists), no exacerbations and a peak flow rate of >80% predicted, may be achieved with the use of combined salmeterol/fluticasone in up to 41% of patients with moderate to severe asthma, compared with only 28% of patients treated with fluticasone alone. Adjustable maintenance dosing with budesonide/formoterol may provide better control when compared with fixed-dosing combination regimens. Other therapies combining effectively with inhaled corticosteroids include slow-release theophylline and leukotriene inhibitors, montelukast and zafirlukast, but LABA are the most efficacious. Molecular interactions between corticosteroids and beta2-adrenoceptors may underlie the clinical added benefits of combination therapy. Corticosteroids may increase the number of beta2-adrenoceptors and their coupling with Gs proteins, while beta2-agonists may induce glucocorticoid receptor nuclear translocation, activate transcription factor/enhancer binding protein C/EBPalpha together with corticosteroids, or phosphorylate corticosteroid receptors. The combination of corticosteroids and LABA potentiates inhibition of interleukin-8 and eotaxin release from human airway smooth muscle cells and granulocyte-macrophage colony-stimulating factor release from epithelial cells, and also the inhibition of airway smooth muscle cell proliferation. It is important to determine whether there is a potentiating effect of combination therapy compared with corticosteroid treatment alone on airway inflammation and airway wall remodelling. Improvements in combination therapy include a once-daily preparation and possible combination of inhaled corticosteroids with newer drugs such as phosphodiesterase IV inhibitors.

Administration, Inhalation↗
PubMed1993

[Effects of a combination therapy consisting of arbekacin and ampicillin of methicillin-resistant Staphylococcus aureus].

Investigations were made on effects of a combination therapy consisting of arbekacin (ABK) and ampicillin (ABPC) against methicillin-resistant Staphylococcus aureus (MRSA). The following conclusions were drawn. 1. A frequency of FIC index to be < or = 0.5 upon a combination therapy consisting of ABK and ABPC against MRSA was 48.7%, hence this therapy showed better antibacterial effects than the other 8 combination therapies consisting of ABK and other antibiotics previously studied. 2. A combination therapy consisting of ABK and ABPC against MRSA was better than any other combination therapy because ABPC had a higher binding affinity with penicillin-binding protein 3 of MRSA, and because a high antibacterial activity of ABPC was maintained during the combination therapy. ABPC did not lose antibacterial activity largely because MRSA dose not produce beta-lactamase, or most of MRSA produces little beta-lactamase activity. 3. Our data indicate that the success of a combination therapy against MRSA depends upon the effects of the drug under sub MIC concentrations.

Aminoglycosides↗
PubMed2005

Prospective trial of endoscopic clips versus combination therapy in upper GI bleeding (PROTECCT--UGI bleeding).

BACKGROUND: It is not known if combination therapy of epinephrine injection and multipolar electrocoagulation or hemoclips are a more efficient or effective treatment for patients with acute nonvariceal upper gastrointestinal (GI) bleeding. METHODS: Adult patients with active nonvariceal upper GI bleeding, a nonbleeding visible vessel, or after removal of an adherent clot findings of active bleeding or a visible vessel were studied. Patients were randomized to either therapy and the outcomes were assessed at 30 days. RESULTS: Forty-seven patients were studied: 26 patients randomized to hemoclips and 21 to combination therapy. There were 22 patients with active bleeding, 13 with a nonbleeding visible vessel, and 12 with an adherent clot. The median duration of endoscopic therapy was 17 min in the hemoclip group versus 20 min for the combination therapy, p= 0.29. Primary hemostasis with successful initial control of bleeding occurred in 26 (100%) of 26 hemoclip patients and 20 (95.2%) of 21 combination therapy patients, p= 0.45. The rebleeding rates were: 4 (15.4%) of 26 hemoclip patients versus 5 (23.8%) of 21 combination therapy patients, p= 0.49. Overall, the length of hospital stay, units of blood transfused, surgery rates, and mortality were not different. CONCLUSIONS: In this prospective, randomized controlled trial of endoscopic hemoclips versus combination therapy in the nonvariceal upper GI bleeding, the efficiency, efficacy, and complications of the two treatment modalities were not significantly different.

Aged↗
PubMed1990

Efficacy of combination therapy with mexiletine and a low dose of propranolol for premature ventricular arrhythmias.

The clinical efficacy of combination therapy with mexiletine and propranolol was investigated in several centres. Twenty-four-hour Holter electrocardiograms were recorded and the severity of ventricular premature beats (VPBs) was assessed on the basis of the frequency of VPBs and according to the criteria of Lown. Forty-eight cases with VPBs received single treatment with mexiletine (300 mg/day). Single treatment with mexiletine was effective in 26 out of 48 cases (54%). Nineteen cases in which the single treatment with mexiletine was not sufficiently effective received combination therapy with mexiletine (300 mg/day) and a low dose of propranolol (30 mg/day). After the combination therapy, significant decreases in the frequency of VPBs were found in 11 out of 19 cases (58%), and lowering of the severity of the grade was found in 4 cases (30.8%). Thirteen out of 19 cases given combination therapy changed to single treatment with propranolol. A change in treatment from combination therapy to single treatment with propranolol was assessed as "undesirable" in 8 out of 13 cases (61.5%). During single treatment with mexiletine, side effects were found in 1 out of 48 cases (2.1%), and during the combination therapy in 1 out of 19 cases (5.2%). Thus, combination therapy with mexiletine and a low dose of propranolol was shown to be useful for patients with VPBs.

Adult↗
PubMedDate not supplied

Combination therapy with Brequinar sodium and cyclosporine synergistically prolongs hamster-to-rat cardia xenograft survival.

The accelerated rejection of hamster cardiac xenografts by Lewis rat recipients is due primarily to a humoral immune response. Traditional immunosuppressive agents, including cyclosporine, FK 506, and rapamycin, have not been effective in prolonging the rejection of xenografts in this model. We have recently examined the ability of the combination of cyclosporine and a new immunosuppressive agent, Brequinar sodium, to prevent the rejection of hamster xenografts. Prolongation of xenograft survival by treatment with Brequinar sodium alone (3 mg/kg/day) was minimally effective, with a median survival of 5.5 days. Conversely, a combination of Brequinar sodium (3 mg/kg/day) and cyclosporine (10 mg/kg/day), was associated with a significant prolongation of median graft survival (> 100 days). A quantitative analysis of the dose-effect relationship of Brequinar sodium and cyclosporine demonstrated a potent synergistic interaction for this combination therapy (combination index < 1). A sharp increase occurred in the binding of immunoglobulin M antibodies at day 4 after transplantation in the serum of untreated and cyclosporine-treated Lewis recipients of cardiac xenografts, whereas a clear decrease occurred in anti-hamster immunoglobulin M antibody production during this period of time in the animals treated by combined immunosuppression. Inhibition of anti-donor immunoglobulin M antibody production, as evaluated by the direct enzyme-linked immunosorbent assay and 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide measurements, extended for more than 100 days after transplantation in the combination therapy group.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗
PubMed1996

Interferon-ribavirin combination therapy for chronic hepatitis C.

Following preliminary reports of small studies that suggested a clinically important enhanced benefit from combination therapy with interferon-alpha (IFN) and ribavirin over IFN monotherapy in chronic hepatitis C, a meta-analysis of data from these studies was performed to estimate the efficacy and tolerability of combination therapy in chronic hepatitis C. Records were obtained from 59 patients who had received combination therapy with IFN 3 MU three times weekly and ribavirin 1000-1200 mg daily for six months and were followed for six months after stopping combination therapy. Outcome measures included the percentage of patients showing ALT normalization and HCV-RNA negativity six months after therapy (sustained response) and the percentage of patients stopping therapy because of side effects. Sustained response was observed in 21% of IFN nonresponders and in 60% of patients who had relapsed after IFN. For naive patients, the estimated sustained response rate was 52%; the observed response rate was 46%. No serious adverse effects were noted; less than 10% of patients discontinued study medication. This meta-analysis of IFN-ribavirin combination therapy for chronic hepatitis C suggests that combination therapy results in a two- to threefold greater efficacy than IFN monotherapy, whereas side effects are similar to IFN monotherapy, with the exception of ribavirin-induced anemia. Interferon-ribavirin combination therapy might become the next step in antiviral therapy for chronic hepatitis C.

Antiviral Agents↗
PubMedDate not supplied

Efficacy of combination therapy in non-insulin dependent diabetes mellitus.

Secondary failure of oral hypoglycaemic agents raises the dilemma of whether to institute therapy with insulin alone, or in combination. We reviewed our experience of combination therapy following secondary failure of oral hypoglycaemic therapy. Seventeen subjects were receiving combination therapy for 6 months or more. Such treatment was associated with a significant fall in HbA1C--from 10.7 +/- 0.38 per cent to 8.3 +/- 0.35 per cent (p < 0.01) after 6 months and remained significantly reduced at 12 months (8.7 +/- 0.34 per cent (p < 0.01)). Mean body weight, systolic and diastolic blood pressure were unchanged during treatment with adjuvant insulin therapy. Insulin therapy is a useful adjunct in the daily management of subjects with NIDDM who experience secondary failure of oral hypoglycaemic agents.

Aged↗
PubMed2026

Pricing Combination Therapies: A Systematic Review of Value Attribution, Cost-Sharing Mechanisms and Policy Frameworks.

BACKGROUND: Combination therapies are increasingly central to modern pharmacotherapy, particularly in oncology and other high-burden diseases. However, pharmaceutical pricing and reimbursement systems remain largely designed for single-product-single-indication interventions. When multiple patented medicines are used together, especially when owned by different manufacturers, conventional pricing frameworks may struggle to align prices with the value of the combination while preserving incentives for innovation and timely patient access. OBJECTIVE: To identify, describe, and critically assess the methods, models, and policy frameworks proposed in the literature to establish prices for combination therapies, with particular attention to value attribution mechanisms, cost-sharing arrangements between manufacturers, and budget impact considerations. METHODS: A systematic literature review was conducted in accordance with PRISMA guidelines and a pre-registered Open Science Framework protocol. Searches were performed in MEDLINE, Scopus, Web of Science, EconLit, CRD databases, and grey literature sources for publications up to July 2025. Eligible studies analysed pricing approaches, economic models, reimbursement mechanisms, or policy frameworks relevant to combination therapies, including more recent multi-indication pricing literature. Given the heterogeneity of the literature, findings were synthesized using a structured narrative and thematic approach. RESULTS: Sixty-nine studies met the inclusion criteria. The literature was dominated by conceptual and policy analyses, with relatively few empirical or implementation-oriented studies. Value attribution emerged as the central methodological challenge in pricing combination therapies. Several complementary approaches were proposed to operationalise value attribution, including adaptations of indication- or pathway-based pricing, manufacturer cost-sharing arrangements, managed entry agreements, and outcome-based reimbursement mechanisms. Empirical evidence suggests that health systems continue to rely primarily on pragmatic and often partial solutions rather than fully specified pricing frameworks. A complementary review of the multi-indication pricing literature indicates that, although the two fields address different pricing problems, they share important methodological and institutional lessons that can inform the development of pricing frameworks for combination therapies. CONCLUSIONS: The literature provides a growing repertoire of conceptual approaches for pricing combination therapies but limited empirical evidence on implementation. Pricing frameworks should place value attribution at their core while combining complementary policy mechanisms adapted to national pricing and reimbursement systems. Lessons from multi-indication pricing provide a valuable foundation but require additional governance mechanisms to address value attribution, multi-manufacturer negotiation, and implementation challenges specific to combination therapies.

Journal Article↗
PubMed2004

A comparison of treatments of squamous cell carcinoma of the base of tongue: surgical resection combined with external radiation therapy, external radiation therapy alone, and external radiation therapy combined with interstitial radiation.

PURPOSE: The outcomes of patients treated at a single institution over a specific time frame using three different therapeutic approaches for cancer of the base of tongue were reviewed. METHODS AND MATERIALS: Between 1992 and 1998, 53 patients were treated with curative intent for base of tongue cancer. Seventeen patients underwent surgical resection with postoperative radiation therapy, 16 patients received definitive external radiation therapy only, and 20 patients were treated with external and interstitial radiation, with neck dissection in 16 of those patients. Local control, survival, and functional status were assessed with each approach. RESULTS: The 5-year actuarial local control and survival for the surgically treated patients were 74% and 44%, respectively. The patients treated with external radiation therapy alone had local control of 28% and 5-year survival of 24%. The patients treated with external and interstitial radiation with neck dissection as indicated had 5-year actuarial local control of 87% and survival of 33%. Survival was not statistically different between the three treatment approaches (p=0.0995) but local control was worse in the definitive external radiation group (p < 0.0001). Speech and swallowing function among the long-term survivors was superior in the definitively irradiated patients compared with the operated patients. CONCLUSION: In this retrospective analysis, survival and local control was lowest in the patients treated with external radiation alone, however, patient selection likely played an important role. Local control was far better with surgical treatment and with external combined with interstitial radiation but survival remains less than 50% with each approach. Surgical treatment was superior for patients with T4 disease. Functional status was higher in the long-term survivors treated nonsurgically.

Brachytherapy↗
PubMed2006

[A case of hepatic metastases of sigmoid colon cancer which completely responded to systemic l-leucovorin/5-FU therapy and oral LV/UFT combination therapy].

A 73-year-old man was admitted for sigmoid colon cancer with multiple hepatic metastases. The patient underwent a sigmoidectomy only, because of bronchial asthma. Then, l-leucovorin (375 mg/body) and 5-FU (750 mg/body) were injected every week. After 2 cycles (1 cycle: 6 weeks of therapy followed by a 2-week treatment break), CT scanning showed almost a complete response, without side effects such as nausea, vomiting, diarrhea and bone marrow suppression. Then, oral administration of LV and UFT was started (LV 75 mg/body/day, UFT 450 mg/body/day. After 2 weeks of therapy, there was a 1-week treatment break), and 2 years after operation this therapy was stopped because the complete response on CT scanning continued.

Administration, Oral↗
PubMed2002

[Combination therapy of disease-modifying antirheumatic drugs(DMARDs) in rheumatoid arthritis].

The early suppression of disease activity during the first 2 years in rheumatoid arthritis (RA) has been reported to be exclusively important to prevent joint destruction and functional decline. Since single disease-modifying antirheumatic drugs(DMARDs) therapy is still disappointing, many rheumatologists today advocated a more aggressive approach using combinations of classic DMARDs. Many clinical trials on combination therapy have been reported and most studies of combination therapy focused on the efficacy of a treatment strategy. Therefore, the possible synergistic action of combination of drugs has not been demonstrated. Among combination of therapy of classical DMARDs, only few trials demonstrated the efficacy of combination therapy. The incidence of adverse effects among 341 RA patients was investigated by our department. The incidence of adverse effect in combination therapy revealed 36.4% which was not statistically different from that in monotherapy(33.6%, p = 0.41). The recent studies on combination therapy on classical DMARDs are not encouraging, however, the combination therapy for patients with early RA, drugs utilizing immunosuppressant, biologics and other newly developed drugs will still have a chance to expect a potent efficacy for RA.

Antirheumatic Agents↗
PubMed1983

Valproate-ethosuximide combination therapy for refractory absence seizures.

Five patients had absence seizures refractory to treatment with either ethosuximide or valproate sodium. To determine their response to combination therapy with the two drugs, four of the five had serial 24-hour intensive monitoring studies that included cable telemetric EEG recording, closed-circuit television observation, and frequent antiepileptic drug (AED) serum level determinations. The resultant data confirmed the clinical and EEG effects of serial alterations in AED programs. All five became seizure free with combination therapy. Combination therapy with ethosuximide and valproate should be considered in patients whose absence seizures do not respond to standard therapeutic measures.

Adolescent↗
PubMed1999

Poor reduction of HIV-1 RNA titres in nucleoside reverse transcriptase inhibitor experienced patients treated with indinavir combination therapy.

OBJECTIVES: The long term effectiveness of combination therapy at reducing viral loads in seminal fluid and blood plasma obtained from HIV-1 infected men who had undergone previous antiretroviral therapy was assessed. METHODS: Samples of semen and blood were obtained from a cohort of 12 nucleoside reverse transcriptase inhibitor experienced men before and during 25-68 weeks of combination therapy, which included the protease inhibitor indinavir. HIV-1 RNA titres present in the cell free blood and seminal plasma samples were determined using the nucleic acid sequence based amplification (NASBA)/Nuclisens assay system. RESULTS: Viral RNA was detected in 9/12 and 7/12 baseline blood plasma and seminal plasma samples, with median viral titres of 10(4.81) and 10(4.56) per ml, respectively. By the end of the study period the detection rates of HIV RNA in the blood and seminal plasma samples were 5/12 and 2/12, respectively, with the median viral titres below the assay cut off level for both sample types. Of the nine patients who had detectable viral RNA in the baseline sample, only three cleared virus from both compartments by the end of the study. CONCLUSIONS: These data show that stable reduction of blood and seminal fluid viral titres is not achievable in a significant proportion of nucleoside reverse transcriptase inhibitor experienced men.

Drug Therapy, Combination↗
PubMed2003

Multiple fixed drug eruption with interferon/ribavirin combination therapy for hepatitis C virus infection.

Interferon/ribavirin combination therapy is the treatment of choice for chronic hepatitis C virus (HCV) infection. Cutaneous reactions to inferferon therapy, both local and distant from the injection site, are not uncommon. Eczematous and lichenoid reactions are most commonly reported. Interferon therapy has also been associated with the occurrence or worsening of a number of dermatologic disorders. We report the case of a 54-year-old man undergoing treatment with interferon/ribavirin combination therapy for hepatitis C who developed a multiple fixed drug eruption associated with interferon injections. To our knowledge, this is the first known reported case of a multiple fixed drug reaction triggered by interferon.

Antiviral Agents↗
PubMed1987

Beta-adrenoceptor stimulating and blocking agents in essential hypertension: single and combined therapy with terbutaline and metoprolol.

Single and combined therapy with terbutaline (10 mg/day) and metoprolol (200 mg/day) was assessed over 8 weeks in a double-blind parallel study in a total of 36 patients with essential hypertension grade I-II according to WHO criteria at rest and during exercise. Blood pressure was comparably reduced with metoprolol and terbutaline (I) and metoprolol alone (II) at rest as well as during exercise. Under terbutaline (III), only diastolic blood pressure decreased during exercise. The responder rates (greater than or equal to 10% reduction in diastolic blood pressure) at rest were 58% in I, 63% in II and significantly lower in III at 42%. Heart rate was not affected in I and III but decreased significantly with metoprolol. While therapy with metoprolol resulted in an increase of noradrenaline and a fall of plasma renin activity after 8 weeks, these parameters remained unchanged in I and III. Therapy was well tolerated in all groups. Terbutaline in the chosen dosage slightly decreased diastolic blood pressure and did not increase heart rate. Metoprolol is an effective antihypertensive agent resulting in a heart rate decrease. Under combined therapy, there is no additional blood pressure decrease, but the heart rate remains unaffected.

Adult↗
PubMed1996

Effects of combination therapy with interferon and ofloxacin on chronic type C hepatitis: a pilot study.

Interferon is effective in only a limited number of patients with the 1b type of hepatitis C virus (HCV), indicating that a combination therapy with other antiviral drugs may be essential to obtain better results. In the present pilot study, the effects of a combination therapy with interferon (IFN) and an antibacterial drug, ofloxacin, were analysed. Ten patients with chronic type C hepatitis received the combination therapy (combination group). Six million units of natural IFN-alpha were administered daily for 3 weeks and then three times a week for 21 weeks. The combination therapy was initiated at the beginning of the eighth week of IFN treatment and 600 mg ofloxacin per day was administered for 12 weeks. As a control, changes in HCV-RNA were also analysed in patients who were treated with only IFN for the same period (IFN-alone group). In the combination group, serum transaminase levels and the titres of HCV decreased significantly with ofloxacin administration. Such changes were not observed in the IFN-alone group. The incidence of HCV-negativity at the end of ofloxacin administration of the combination group was significantly higher than in the IFN-alone group. The complete response rate was twice as high in the combination group as in the IFN-alone group. In two patients who did not respond well to the IFN-alone treatment, ofloxacin administration was commenced after the 24th week. Serum transaminase levels were normalized and HCV-RNA became negative in these two patients after the administration of ofloxacin. These results suggest that combination therapy with IFN and ofloxacin may be an effective treatment for chronic type C hepatitis.

Adult↗
PubMed1993

[Pulmonary cryptococcosis treated by combination therapy of fluconazole plus flucytosine].

The efficacy of the combination therapy of fluconazole plus flucytosine against pulmonary cryptococcosis was investigated. The minimal inhibitory concentrations of antifungal agents were measured by growth inhibition on Yeast-morphology agar plates, and the fractional inhibitory concentration index of each antifungal combination were calculated by checker-board titration. Eight of Cryptococcus neoformans clinical isolates showed sensitivity for AMPH, 5-FC, MCZ and ITZ. C. neoformans showed resistance against FLCZ. The combination of FLCZ plus 5-FC showed synergistic effect against C. neoformans. Three cases of pulmonary cryptococcosis were treated by combination therapy of fluconazole plus flucytosine. After treatment, C. neoformans isolates were eradicated and the chest X-ray improved remarkably. The combination therapy of fluconazole plus flucytosine was effective for the treatment of pulmonary cryptococcosis.

Aged↗