Part Of Combination Therapy Research Articles

Targeted Induction of Apoptosis in Cancer Management: The Emerging Role of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptor Activating Agents

Targeted induction of programmed cell death or apoptosis via the extrinsic apoptotic pathway represents an unexploited therapeutic strategy to destroy cancer cells. The activation of cell surface receptors by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) results in direct stimulation of apoptotic signaling pathways (extrinsic stimulation). Molecules that directly activate these receptors, such as agonistic monoclonal antibodies to the TRAIL receptors and recombinant TRAIL, are being developed as monotherapies and as part of combination therapies with existing chemotherapeutic drugs and other therapeutic modalities. This article examines the TRAIL receptors as potential targets for activating the TRAIL-mediated apoptosis pathway and presents the current status of novel therapeutics that exploit this pathway, particularly focusing on agonistic monoclonal antibodies to the TRAIL receptors. The preclinical activity, the status of ongoing evaluations, and the potential clinical impact of these novel agents are reviewed.

An overview of the pharmacology and clinical efficacy of indapamide sustained release

The relationship between blood pressure (BP) and cardiovascular risk is clearly established; hypertension increases the rate of cardiovascular. High systolic blood pressure (SBP) may be the main parameter involved in cardiovascular morbidity and mortality. The benefit of lowering BP, particularly with diuretics has been proven in many outcome studies. Indapamide, a thiazide-type diuretic, was available for many years at a dosage of 2.5 mg in an immediate release formulation. A new sustained release (SR) formulation has been developed in order to allow the same antihypertensive efficacy with a better acceptability profile. This paper reviews the pharmacology of indapamide 1.5 mg SR from the bench to the bedside. Indapamide has a dual mechanism of action: diuretic effect at the level of the distal tubule in the kidney and a direct vascular effect, both of which contribute to the antihypertensive efficacy of the drug. The SR formulation contains a hydrophilic matrix, which delivers a smoother pharmacokinetic profile. This avoids unnecessary plasma peak concentrations, which may be associated with side effects. Indapamide SR has now been extensively used in hypertensive patients, including those at increased risk, for example elderly or diabetic patients. It has been shown to decrease BP, particularly SBP, with 24-h efficacy, allowing a once-daily dosage. Studies have demonstrated BP lowering to be at least as effective as all major therapeutic classes including the more recent antihypertensive drugs. Beyond BP decrease, indapamide SR has also been shown to protect against hypertensive target-organ damage in the heart and the kidney and to have a favorable metabolic profile. A broad evidence-base has accumulated to support the benefit of indapamide 1.5 mg SR in hypertensive patients, alone or as part of combination therapy, as recommended by the majority of guidelines.

Amplification ofPlasmodium falciparumMultidrug Resistance Gene 1 in Isolates from Gabon

The study of molecular markers of drug resistance is particularly important in surveillance studies of drugs, such as mefloquine, that still retain efficacy in sub-Saharan Africa yet have encountered resistance elsewhere. In a recent study in Thailand, we identified amplification of the Plasmodium falciparum multidrug resistance gene 1 (pfmdr1) as being the most important predictor of in vitro drug resistance and in vivo failure of mefloquine monotherapy. Here we report amplification of pfmdr1 in >5% of patient samples from Lambarene, Gabon, collected in 1995. None of the samples collected 7 years later showed pfmdr1 amplification, suggesting that parasites with increased numbers of pfmdr1 copies have not substantially spread through the population. Nevertheless, the detection of multicopy pfmdr1 in African parasites suggests a high potential for rapid selection for resistance, implying that mefloquine use in Africa should be considered only as part of combination therapy.

Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis

Mycobacterium tuberculosis and Yersinia pestis, the causative agents of tuberculosis and plague, respectively, are pathogens with serious ongoing impact on global public health and potential use as agents of bioterrorism. Both pathogens have iron acquisition systems based on siderophores, secreted iron-chelating compounds with extremely high Fe3+ affinity. Several lines of evidence suggest that siderophores have a critical role in bacterial iron acquisition inside the human host, where the free iron concentration is well below that required for bacterial growth and virulence. Thus, siderophore biosynthesis is an attractive target in the development of new antibiotics to treat tuberculosis and plague. In particular, such drugs, alone or as part of combination therapies, could provide a valuable new line of defense against intractable multiple-drug-resistant infections. Here, we report the design, synthesis and biological evaluation of a mechanism-based inhibitor of domain salicylation enzymes required for siderophore biosynthesis in M. tuberculosis and Y. pestis. This new antibiotic inhibits siderophore biosynthesis and growth of M. tuberculosis and Y. pestis under iron-limiting conditions.

Pegylated liposomal doxorubicin: Proof of principle using preclinical animal models and pharmacokinetic studies

Encapsulation of doxorubicin in polyethylene glycol-coated liposomes (Doxil/Caelyx [PLD]), was developed to enhance the safety and efficacy of conventional doxorubicin. The liposomes alter pharmacologic and pharmacokinetic parameters of conventional doxorubicin so that drug delivery to the tumor is enhanced while toxicity normally associated with conventional doxorubicin is decreased. In animals and humans, pharmacokinetic advantages of PLD include an increased area under the plasma concentration-time curve, longer distribution half-life, smaller volume of distribution, and reduced clearance. In preclinical models, PLD produced remission and cure against many cancers including tumors of the breast, lung, ovaries, prostate, colon, bladder, and pancreas, as well as lymphoma, sarcoma, and myeloma. It was also found to be effective as adjuvant therapy. In addition, it was found to cross the blood-brain barrier and induce remission in tumors of the central nervous system. Increased potency over conventional doxorubicin was observed and, in contrast to conventional doxorubicin, PLD was equally effective against low- and high-growth fraction tumors. The combination of PLD with vincristine or trastuzumab resulted in additive effects and possible synergy. PLD appeared to overcome multidrug resistance, possibly as the result of increased intracellular concentrations and an interaction between the liposome and P-glycoprotein function. On the basis of pharmacokinetic and preclinical studies, PLD, either alone or as part of combination therapy, has potential applications to treat a variety of cancers.

Analysis of treatment for small cell cancer of the bladder and report of three cases

Objectives To present our experience with 3 patients with small cell cancer (SCC) of the bladder who were treated with different modalities and review the literature for patients undergoing primary chemoradiotherapy. SCC of the bladder is a rare tumor, with patients commonly presenting with metastatic disease. Surgery, radiotherapy, and chemotherapy, either alone or as part of combined therapy, have been used. Because of the rarity of this disease, no prospective studies evaluating the most effective treatment have been done. Methods The medical records of 3 patients diagnosed with SCC of the bladder at our institution were reviewed. Additionally, we reviewed published reports to identify all cases of SCC of the bladder treated with primary chemoradiotherapy. Results Three patients with SCC of the bladder were identified at our institution. A total of 23 patients with SCC of the bladder who were treated with primary chemoradiotherapy were identified: 22 in published reports and 1 at our institution. Patients presented with muscle-invasive disease (17%), extravesical disease only (26%), and metastatic disease (52%). Multiagent chemotherapy was administered to most patients. The reported median radiation dose was 6000 cGy. A total of 16 patients (70%) were alive at a median follow-up of 34 months. The median survival of patients had not yet been reached in this study at the last follow-up. We did not find any reports of SCC recurrence in the bladder, and the bladder was preserved in most patients (87%). Conclusions SCC of the bladder should be viewed as a systemic disease, because most patients present with metastatic disease. Primary chemoradiotherapy appears to be an effective treatment modality. Prospective studies are needed to evaluate the optimal treatment further.

Addition of bicalutamide 80 mg to LHRH-agonist monotherapy in patients with advanced prostate cancer: Impact on quality of life

4703 Background: Bicalutamide (‘Casodex’) 80 mg (licensed dose in Japan) is being evaluated as part of combination therapy in patients (pts) with previously untreated advanced prostate cancer in an ongoing Japanese double-blind Phase III trial. Interim analysis after all pts had completed at least 6 months' follow-up (median follow-up 15 months) showed that first-line treatment with bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist significantly improved the prostate-specific antigen normalization rate at 12 weeks and reduced the risk of treatment failure and disease progression compared with LHRH-agonist monotherapy, without compromising tolerability (Proc Am Soc Clin Oncol 2003; 22: 422 [abs 1695]). We now report quality-of-life (QoL) findings during the first 24 weeks of treatment. Methods: Pts with previously untreated advanced (stage C/D) prostate cancer were randomized to receive bicalutamide 80 mg od (n=102) or placebo (n=101), in addition to an LHRH agonist. QoL was assessed using the Japanese version of the Functional Assessment of Cancer Therapy (FACT), a general questionnaire (FACT-G) assessing physical, social/family, emotional and functional wellbeing, plus a disease-specific subscale for prostate cancer symptoms (FACT-P); this was completed at baseline and at Weeks 1, 5 and 24. Results: The questionnaire collection rate at Week 24 was 93.1% in the bicalutamide 80 mg group and 89.1% with placebo. Total FACT scores showed no clear improvement in QoL in either treatment group at each time point. Mean FACT-P scores (specific to prostate cancer symptoms) increased by 4.64 and 3.10 from baseline to Week 24 in the bicalutamide 80 mg and placebo groups, respectively (difference 1.54;95%CI-1.03,4.11). Analyses of FACT-P scores using generalized estimating equations revealed a greater overall improvement with bicalutamide 80 mg compared with placebo (p=0.051). Conclusions: Compared with LHRH-agonist monotherapy, bicalutamide 80 mg in combination with an LHRH agonist improves symptom-related QoL in pts with previously untreated advanced prostate cancer. ‘Casodex’ is a trademark of the AstraZeneca group of companies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Around 30 pharma companies including AstraZeneca Around 30 pharma companies including AstraZeneca AstraZeneca

Addition of bicalutamide 80 mg to LHRH-agonist monotherapy in patients with advanced prostate cancer: Impact on quality of life

4703 Background: Bicalutamide (‘Casodex’) 80 mg (licensed dose in Japan) is being evaluated as part of combination therapy in patients (pts) with previously untreated advanced prostate cancer in an...

Progress with thiazolidinediones in the management of type 2 diabetes mellitus

Background: Much progress has been made in the field of medicine within the past 20 years; however, cardiovascular outcomes in patients with diabetes mellitus have not improved to a corresponding degree. Although numerous treatments are available for the management of type 2 diabetes, current approaches appear to address the spectrum of the disease and its complications insufficiently. Objectives: This article reviews evidence for the minimal effects of standard antidiabetic treatments on the macrovascular complications associated with type 2 diabetes, discusses the improvements in markers of cardiovascular risk seen with the thiazolidinediones (TZDs), and explores the rationale for their earlier use. Methods: Relevant articles and guidelines on the use of oral antidiabetic agents in the treatment of type 2 diabetes were identified through a search of MEDLINE for the past 15 years using the terms cardiovascular, insulin resistance, metabolic syndrome, metformin, sulfonylurea, type 2 diabetes, and thiazolidinediones. The reference lists of selected articles also were searched. Articles chosen for review were required to assess clinically important outcomes or surrogate markers that have been shown to have a direct link to clinically important outcomes. Results: The data reviewed suggest that the sulfonylureas and/or metformin are able to reduce microvascular complications associated with type 2 diabetes but do not substantially affect macrovascular complications. In contrast, the TZDs demonstrate insulin-sensitizing effects attributable to their novel mechanism of action on the peroxisome proliferator-activated receptor gamma. The resulting reduction in insulin resistance appears to improve many of the metabolic and cardiovascular pathways influenced by insulin activity. Blood pressure, vascular and coagulation defects, lipid abnormalities, and beta-cell function have been found to improve in patients receiving TZD treatment. For example, there are reports of significant reductions in levels of C-reactive protein ( P < 0.01); small, dense low-density lipoprotein cholesterol particles ( P < 0.05); and circulating free fatty acids ( P < 0.003), in addition to improvements in the proinsulin-to-insulin ratio ( P < 0.05). Conclusions: In this review of the literature, use of TZDs as monotherapy or as part of combination therapy has been associated with effective glycemic control and reductions in markers of various macrovascular complications of type 2 diabetes. Although outcomes trials are ongoing, the preliminary effects of TZD therapy are promising and suggest that earlier use of TZDs in the pharmacologic management of type 2 diabetes has the potential to minimize severe disease sequelae.

Low dose intranasal lysine-aspirin in patients with aspirin-sensitive nasal polyps

Rationale Intranasal lysine-aspirin is a potential alternative to oral desensitization in patients with aspirin-sensitive nasal polyposis. Uncritical trials have suggested its effectiveness 1,2 . We have undertaken the first scientifically controlled trial. Methods Randomized, double blind, placebo controlled, crossover trial using low dose (8mgs) intranasal lysine-aspirin (LAS) in polyp patients who reacted positively to nasal challenge with lysine aspirin. Nasal polyp size was measured using acoustic rhinometry. Patients maintained a daily diary of nasal and chest scores, nasal inspiratory peak flow (NIPF) and peak expiratory flow rate (PEFR). No other polyp therapy was permitted. Results Nine patients completed both phases. Multivariate analysis did not show any significant difference between the placebo or LAS phase. Volume and minimal cross sectional area changes were similar in both phases (p=.587, p=.774). Diary scores were similar (nasal score, p=.82; chest score p=.82; NIPF, p=.44; PEFR, p=.95). Conclusions Low dose intranasal lysine-aspirin over 6 months is not effective in reducing polyp growth, but does not adversely affect asthma. However, nasal biopsies showed a significant reduction in CysLT 1 receptor expression following LAS 3 . This suggests that desensitization occurs at a molecular level, but translation into clinical benefit may require more prolonged LAS use, possibly at higher doses as part of combined therapy.

Repaglinide : a pharmacoeconomic review of its use in type 2 diabetes mellitus.

Repaglinide : a pharmacoeconomic review of its use in type 2 diabetes mellitus.

Emtricitabine/tenofovir disoproxil fumarate.

The nucleoside analogue reverse transcriptase inhibitor (RTI) emtricitabine and the nucleotide analogue RTI tenofovir disoproxil fumarate (tenofovir DF) have each shown antiviral activity against a number of HIV clinical isolates and cell lines. HIV variants with reduced susceptibility to emtricitabine and tenofovir have been selected for in vitro and have also been isolated from patients receiving the agents. Low rates of these variants have been observed in patients experiencing virological failure in large studies of emtricitabine- or tenofovir DF-containing therapy. Co-formulated oral emtricitabine/tenofovir DF was bioequivalent to the two agents as separate formulations in a pharmacokinetic trial in healthy volunteers. There are no published data on the clinical antiviral efficacy of co-formulated oral emtricitabine/tenofovir DF. However, each agent is effective in combination regimens with other drugs. Ongoing studies in antiretroviral-naive patients are evaluating the efficacy of the individual formulations given together in combination with efavirenz or lopinavir/ritonavir. In the latter trial, HIV RNA levels were reduced and CD4+ cell counts were increased at 24 and 48 weeks. Emtricitabine and tenofovir DF are generally well tolerated. Diarrhoea, nausea and vomiting were the most common adverse events reported with coadministered emtricitabine and tenofovir DF as separate formulations as part of combination therapy.

Thalidomide for erythema nodosum leprosum and other applications.

Thalidomide, administered as a sedative and antiemetic decades ago, was considered responsible for numerous devastating cases of birth defects and consequently was banned from markets worldwide. However, the drug remarkably has resurfaced with promise of immunomodulatory benefit in a wide array of immunologic disorders for which available treatments were limited. It is approved by the Food and Drug Administration for erythema nodosum leprosum (ENL). Although the relative paucity of leprosy and ENL worldwide may perceivably limit interest in and knowledge about thalidomide, increasing numbers of new and potential uses expand its applicability widely beyond ENL. Thalidomide, an inhibitor of tumor necrosis factor a, is the best known agent for short-term treatment of ENL skin manifestations, as well as postremission maintenance therapy to prevent recurrence. For this indication, it is effective as monotherapy and as part of combination therapy with corticosteroids. Studies of thalidomide in chronic graft-versus-host disease showed benefit in children and adults as treatment, but not as prophylaxis. The agent has been administered successfully for treatment of cachexia related to cancer, tuberculosis, and human immunodeficiency virus infection, although evidence of efficacy is inconclusive. Thalidomide monotherapy effectively induced objective response in trials in patients with both newly diagnosed and advanced or refractory multiple myeloma. Combination therapy with thalidomide and corticosteroids was also effective in these patients, as well as in treatment of aphthous and genital ulcers. Limited evidence supports the drug's benefit in treatment of Kaposi's sarcoma. Other thalidomide applications include Crohn's disease, rheumatoid arthritis, and multiple sclerosis. Somnolence, constipation, and rash were the most frequently cited adverse effects in studies, but thalidomide-induced neuropathy and idiopathic thromboembolism were critical causes for drug discontinuation. Thalidomide is still contraindicated in pregnant women, women of childbearing age, and sexually active men not using contraception. Clinicians should be conversant with thalidomide in ENL (its primary application) in the natural course of leprosy, as well as in the agent's other applications.

Lopinavir/ritonavir: a review of its use in the management of HIV infection.

Lopinavir/ritonavir: a review of its use in the management of HIV infection.

Intestinal graft-versus-host disease: mechanisms and management.

Allogeneic haematopoietic stem cell transplantation remains the treatment of choice for a number of malignancies. However, graft-versus-host disease (GVHD) has long been regarded as a serious complication of this procedure. Although GVHD may affect any organ, intestinal GVHD is particularly important because of its frequency, severity and impact on the general condition of the patient. Recent studies have led to progressive elucidation of the mechanism of GVHD. Donor T cells are critical for the induction of GVHD, because depletion of T cells from bone marrow grafts effectively prevents GVHD but also results in an increase of leukaemia relapse. It has been shown that the gastrointestinal tract plays a major role in the amplification of systemic disease because gastrointestinal damage increases the translocation of endotoxins, which promotes further inflammation and additional gastrointestinal damage. Consequently, the management of intestinal GVHD (and the intestine itself) is a subject that should be highlighted. In this article, approaches to the prevention of intestinal GVHD are discussed after being classified into three categories: regimens in common clinical use, regimens under investigation and original regimens used at our hospital. The standard regimen that is used most widely for prevention of GVHD is cyclosporin plus short-term methotrexate. Corticosteroids can be added to this regimen but careful consideration of the adverse effects of these hormones should be considered. Tacrolimus is a newer, more potent alternative to cyclosporin. T-cell depletion (TCD) after transplantation has been shown to prevent acute GVHD, however, the survival benefit of TCD has not been as great as expected. Mycophenolate mofetil can be useful for the treatment of acute GVHD as part of combination therapy. Regimens currently under investigation in animal experiments include suppression of inflammatory cytokines and inhibition of T-cell activation, and, specifically at our institution, hepatocyte growth factor gene therapy. The evidence-based therapy used at our institution includes systemic antibacterial therapy (including eradication of intestinal bacteria) to prevent the intestinal translocation of lipopolysaccharide and avoid the subsequent increase of various inflammatory cytokines. In addition, because of the similarities between intestinal GVHD and ulcerative colitis, sulfasalazine, betamethasone enemas and eicosapentaenoic acid have been used to treat intestinal GVHD in some patients.

Clinical relevance of penicillin-resistant Streptococcus pneumoniae.

Streptococcus pneumoniae is the most important respiratory tract pathogen in otitis, sinusitis, bronchitis, and community-acquired pneumonia. Over the past decades, there has been an increase in minimum inhibitory concentrations (MICs) to penicillin. Decreased susceptibility to penicillin is not the same as penicillin resistance. Decreased susceptibility to penicillin has occurred worldwide from dissemination of several resistant pneumococcal clones, and, to a lesser extent, from excessive use of ciprofloxacin, macrolides, and trimethoprim-sulfamethoxazole (TMP-SMX). Currently, penicillin resistance is defined by using a breakpoint of 2 microg/mL or more. Intermediately resistant strains (MIC 1-2 microg/mL) are also relatively sensitive depending on antibiotic concentration. Intermediate antibiotic susceptibility is concentration dependent. Antibiotic concentration at various body sites is determined by pharmacokinetic considerations. Except for very highly resistant strains, the treatment of penicillin-resistant S. pneumoniae causing bacteremia, sinusitis, otitis, bronchitis, or community-acquired pneumonia remains penicillin or any beta-lactam. Only in pneumococcal meningitis caused by penicillin-resistant pneumococci does the clinician have to use care in selecting an antipneumococcal antibiotic with adequate cerebrospinal fluid penetration and favorable kill ratios. Clinicians should be selective in antibiotic selection to minimize further decreases in penicillin susceptibility to S. pneumoniae. This is best achieved by using low-resistance potential antibiotics oral/intravenous mono-therapy at the full recommended dose. Therapeutic failure may occur in using lower doses at certain body sites. Macro-lides as monotherapy or as part of combination therapy should be minimized. Optimal therapy for non-central nervous system pneumococcal infection is with a respiratory quinolone (eg, levofloxacin, gatifloxacin, moxifloxacin), clindamycin, doxycycline, third-generation cephalosporins. For highly resistant pneumococci, levofloxacin, gatifloxacin, moxifloxacin, cefepime, meropenem, vancomycin, or linezolid may be used.

Gemcitabine and targeted therapy in metastatic breast cancer.

Gemcitabine, a new cytotoxic nucleoside analog, has demonstrable single-agent antitumor activity in metastatic breast cancer. Recently, nearly 20 phase II clinical trials of gemcitabine alone or as part of combination therapy have confirmed its role in this disease. As a single agent, gemcitabine leads to response rates ranging from 16% to 37% in either first-line and/or refractory settings. Combined with platinum, taxanes, vinorelbine, and anthracyclines as doublets or triplets, response rates in the range of 50% to 80% have been reported in small phase II clinical trials. The relatively mild toxicity profile of gemcitabine makes it an attractive agent to evaluate in combination with targeted drugs such as trastuzumab, tyrosine kinase inhibitors, and angiogenesis inhibitors, among others. In this review we summarize current available data of gemcitabine in the management of metastatic breast cancer, and provide a perspective of gemcitabine in future clinical research for management of this disease.

Benzamide riboside, a recent inhibitor of inosine 5'-monophosphate dehydrogenase induces transferrin receptors in cancer cells.

Benzamide riboside, a recently discovered inhibitor of IMP dehydrogenase (IMPDH) exhibits oncolytic activity. IMPDH is the key enzyme of de novo guanylate biosynthesis and was shown to be linked with proliferation. Therefore, IMPDH is a very good target for antitumor therapy. In order to be active, benzamide riboside has to be converted to BAD, an NAD analogue that binds to the NAD site on IMPDH. Inhibition of the enzyme by benzamide riboside selectively inhibits tumor cell growth and induces apoptosis in various human tumor cell lines. In this manuscript we describe the induction of the CD71 transferrin receptor in human promyelocytic leukemia HL-60 cells following treatment with benzamide riboside. The results indicate a possible involvement of the iron metabolism in the action of this new compound. Benzamide riboside might be clinically used in the treatment of leukemia and solid tumors, alone or as part of combination therapy. Since transferrin receptors are overexpressed in certain cancers, such as glioma and colon cancer, a combination therapy that includes benzamide riboside in transferrin-coupled liposomes will not only target cancer cells but also leads to suicidal action because benzamide riboside will upregulate transferrin receptors on cancer cells thereby make it accessible to dose-intensive chemotherapy. We therefore believe that benzamide riboside itself or derivatives of benzamide riboside might become an important addition for the treatment to diseases that are otherwise fatal.

Gemcitabine and targeted therapy in metastatic breast cancer

Gemcitabine, a new cytotoxic nucleoside analog, has demonstrable single-agent antitumor activity in metastatic breast cancer. Recently, nearly 20 phase II clinical trials of gemcitabine alone or as part of combination therapy have confirmed its role in this disease. As a single agent, gemcitabine leads to response rates ranging from 16% to 37% in either first-line and/or refractory settings. Combined with platinum, taxanes, vinorelbine, and anthracyclines as doublets or triplets, response rates in the range of 50% to 80% have been reported in small phase II clinical trials. The relatively mild toxicity profile of gemcitabine makes it an attractive agent to evaluate in combination with targeted drugs such as trastuzumab, tyrosine kinase inhibitors, and angiogenesis inhibitors, among others. In this review we summarize current available data of gemcitabine in the management of metastatic breast cancer, and provide a perspective of gemcitabine in future clinical research for management of this disease. Semin Oncol 29 (suppl 11):44-52. Copyright 2002, Elsevier Science (USA). All rights reserved.

Eprosartan: an angiotensin-II receptor antagonist for the management of hypertension.

Eprosartan is a competitive angiotensin-II receptor antagonist with a high affinity for the angiotensin-II subtype 1 receptor. The drug has an elimination half-life of approximately 5 to 9 hours and duration of antihypertensive effect of up to 24 hours. The antihypertensive efficacy of eprosartan has been examined in a number of placebo-controlled, dose-finding, and comparative trials. Results of these clinical trials have consistently shown statistically significant differences in antihypertensive efficacy favoring eprosartan doses of 400 mg or greater per day over placebo. Eprosartan was also shown to be at least as effective as enalapril at lowering blood pressure in patients with mild to severe hypertension. The frequency of adverse events observed with eprosartan has been similar to that seen with placebo. In addition, there are no clinically significant drug interactions associated with eprosartan. Given the excellent tolerability and drug-interaction profiles of eprosartan, the use of this agent may help to improve patient compliance to a drug regimen. In addition, eprosartan may be particularly advantageous when used as a part of combination therapy for the management of hypertension.