Olmesartan medoxomil: an angiotensin II-receptor blocker

BACKGROUND: Regulation of the activity of the renin-angiotensin-aldosterone system has become important in the management of cardiovascular disease. Olmesartan medoxomil (CS-866) is the newest selective angiotensin II-receptor blocker (ARB) to be approved for the treatment of hypertension. OBJECTIVE: This review describes the mechanism of action, pharmacokinetics, adverse-effect profile, drug-interaction potential, and dosing of olmesartan medoxomil. The results of relevant clinical efficacy and safety trials are also discussed. METHODS: This review is based on data from published clinical efficacy and safety trials and abstracts of conference presentations. To identify appropriate English-language publications for review, MEDLINE (1966-October 2002) and EMBASE (1990-2002) were searched using the terms olmesartan medoxomil, CS-866, angiotensin II-receptor blocker, and hypertension. RESULTS: Olmesartan medoxomil has been reported to be an effective agent for the treatment of hypertension. Its blood pressure-lowering effects were comparable to those of other antihypertensive agents and other ARBs. Effects were seen as early as 2 weeks and persisted when olmesartan medoxomil was administered long term (for 1 year). The maximum recommended daily dose is 40 mg, except in the presence of severe renal insufficiency (creatinine clearance <20 mL/min) or moderate hepatic insufficiency (Child-Pugh score 7-9), when the daily dose should not exceed 20 mg. Olmesartan medoxomil was well tolerated. The most commonly reported adverse effect occurring significantly more often with olmesartan medoxomil than with placebo was dizziness (seen in approximately 3% of patients). The occurrence of clinically significant drug interactions was minimal. CONCLUSIONS: Based on the available literature, olmesartan medoxomil is an effective ARB for the treatment of hypertension, with a favorable adverse-effect and drug-interaction profile.     

Clinical efficacy and tolerability of olmesartan

Background: Olmesartan medoxomil is an angiotensin II receptor antagonist that selectively and competitively inhibits the angiotensin 11 type 1 receptor.Objective: This article reviews the results of some key studies that assessed the efficacy and tolerability of olmesartan in patients with hypertension.Methods: Olmesartan has been investigated in several clinical studies. This article reports on data from 1 such study with a prospective, randomized, double-blind, placebo-controlled, parallel-group, dose-finding design in patients with mild to moderate hypertension (baseline mean sitting diastolic blood pressure, 100–114 mm Hg). The results from a meta-analysis of 7 randomized, double-blind, placebo-controlled studies are also presented.Results: In the dose-finding study, 792 patients were randomized to olmesartan (2.5–80 mg) or placebo once daily, and changes were recorded in trough mean sitting diastolic and systolic blood pressures from baseline to the end of a 12-week treatment period. For the meta-analysis, 3055 patients were randomized to treatment; 2511 received olmesartan. In the dose-finding study as well as in the meta-analysis, olmesartan (2.5–80 mg once daily) produced a dose-dependent decrease in diastolic and systolic blood pressures, and at a dose of 10 to 80 mg showed significant superiority in reducing diastolic blood pressure over placebo (P < 0.05). The 20-mg dose was considered optimal, with a responder rate of 70%. Furthermore, in a 2-year study with 462 patients, olmesartan had a good safety profile and was well tolerated. The results of the clinical studies in >3000 patients receiving olmesartan showed that the frequency and profile of adverse events with olmesartan were generally similar to those with placebo; the frequency of adverse events was not dose related. Olmesartan, with or without hydrochlorothiazide, was well tolerated over 2 years of treatment.     

Clinical profiles of new angiotensin II receptor blockers: telmisartan, olmesartan medoxomil, and irbesartan

Clinical use of type 1 angiotensin II receptor blockers(ABRs) is rapidly increasing because of their high safety as well as excellent efficacy. Recent clinical trials have demonstrated that telmisartan at a daily dose of 20-80 mg, olmesartan medoxomil at 10-40 mg, and irbesartan at 150-300 mg are effective and safe for the treatment of essential hypertension, severe hypertension and hypertension associated with renal diseases. These ARBs are similar to ACE inhibitors in terms of antihypertensive efficacy, but lack the adverse effect of cough. Long-term effects should be compared among ARBs, ACE inhibitors, and other antihypertensive drugs.     

Candesartan cilexetil: an angiotensin II receptor blocker

OBJECTIVE: To summarize and critique the medical literature on candesartan cilexetil, an angiotensin II receptor blocker (ARB). DATA SOURCES: MEDLINE searches (January 1966-January 1999) and manufacturer prescribing literature were used to identify articles on candesartan cilexetil. Bibliographies were also reviewed for germane articles. STUDY SELECTION: Study and review articles describing the chemistry, human pharmacology, pharmacodynamics, pharmacokinetics, placebo-controlled trials, comparative trials, and clinical application of candesartan cilexetil based on the published literature and premarketing clinical trials were reviewed. DATA EXTRACTION: All literature on the use of candesartan cilexetil for treating hypertension and congestive heart failure were included. DATA SYNTHESIS: ARBs are a new class of drugs with increasing use in treating hypertension. Studies are ongoing to determine the role of these agents in preventing remodeling after myocardial infarction and in patients with congestive heart failure. Candesartan cilexetil is among the newest drugs in the class that includes losartan, irbesartan, and valsartan. Candesartan cilexetil has more than 1000 times more affinity for the angiotensin II, type AT1 receptor ARBs, and the binding affinity and competitive angiotensin II receptor antagonism is stronger than that of losartan. Clinical studies in patients with hypertension have demonstrated that candesartan cilexetil, in doses of 4-16 mg, is more effective in reducing sitting diastolic blood pressure than are placebo and losartan 50 mg. Candesartan cilexetil has demonstrated reductions in blood pressure comparable to those of enalapril, with the rate of adverse events greater in the enalapril group. Dosage adjustments are not necessary in elderly patients or in patients with mild hepatic or renal dysfunction. In diabetic patients, blood glucose, hemoglobinA1c, and serum lipids are not affected. The clinical studies demonstrated that the adverse effect profile of candesartan cilexetil was similar to that of placebo and there were no dose-dependent adverse effects. CONCLUSIONS: Candesartan cilexetil provides an alternative antihypertensive therapy that is well tolerated and effective in reducing blood pressure in a wide range of patients. Due to its greater binding affinity to the angiotensin II receptor, candesartan cilexetil appears to have a longer antihypertensive effect than losartan. This may be advantageous in decreasing morbidity and mortality associated with hypertension, although further studies are required to validate this potential advantage.     

Olmesartan compared with other angiotensin II receptor antagonists: Head-to-head trials

Background: Drugs that block the renin-angiotensin system represent one of the most significant therapeutic interventions available for the treatment of hypertension. The angiotensin II receptor antagonists (AIIRAs), also known as sartans, are one such class of drugs that block the effects of angiotensin II by antagonizing the angiotensin II type 1 receptor. Olmesartan is the newest member of this class.Objective: The present article reviews 3 head-to-head trials directly comparing the antihypertensive efficacy of olmesartan with that of 4 other AURAS, at recommended maintenance doses, already in clinical use for the treatment of hypertension.Results: In the first study, olmesartan 10 mg/d was compared with losartan 50 mg/d in 316 patients with mild to moderate hypertension (mean baseline diastolic blood pressure [DBP], 95–114 mm Hg). Dosage was doubled at week 4 and hydrochlorothiazide was added at week 12 if blood pressure response was inadequate. Olmesartan was significantly more effective than losartan with respect to the reduction in blood pressure at weeks 2, 4, and 12, and to the responder rate at weeks 2 and 4 (with the starting dose of the respective drug). In a second study, olmesartan 20 mg/d was shown to be significantly more effective than losartan 50 mg/d, valsartan 80 mg/d, and irbesartan 150 mg/d in 588 patients with mild to moderate hypertension (mean sitting baseline DBP, 100–115 mm Hg) (P ⩽ 0.05). At week 2, the reduction in blood pressure observed with olmesartan was significantly greater than that of the comparator treatments (P ⩽ 0.05). The superiority of olmesartan was maintained at week 8. The third study involved 643 evaluable patients with moderate to severe hypertension (mean DBP, 100–120 mm Hg; mean systolic blood pressure, >150 mm Hg). Olmesartan 20 mg/d was more effective than candesartan 8 mg/d in lowering 24-hour blood pressure at week 8 (P ⩽ 0.05). Most of this treatment effect was evident after only 1 or 2 weeks, with greater reductions in blood pressure compared with candesartan.Conclusions: These data indicate that, at the doses studied, olmesartan is more effective than other AIIRAs tested at their recommended doses, in terms of reduction of cuff or 24-hour ambulatory blood pressure, in patients with essential hypertension. These differences in blood pressure reduction between these agents may be clinically relevant and have important long-term implications. Additional studies will further define the role of olmesartan in the management of cardiovascular diseases, such as atherosclerosis.     

Sustained 24-hour blockade of the renin-angiotensin system: a high dose of a long-acting blocker is as effective as a lower dose combined with an angiotensin-converting enzyme inhibitor

Whether a higher dose of a long-acting angiotensin II receptor blocker (ARB) can provide as much blockade of the renin-angiotensin system over a 24-hour period as the combination of an angiotensin-converting enzyme inhibitor and a lower dose of ARB has not been formally demonstrated so far. In this randomized double-blind study we investigated renin-angiotensin system blockade obtained with 3 doses of olmesartan medoxomil (20, 40, and 80 mg every day) in 30 normal subjects and compared it with that obtained with lisinopril alone (20 mg every day) or combined with olmesartan medoxomil (20 or 40 mg). Each subject received 2 dose regimens for 1 week according to a crossover design with a 1-week washout period between doses. The primary endpoint was the degree of blockade of the systolic blood pressure response to angiotensin I 24 hours after the last dose after 1 week of administration. At trough, the systolic blood pressure response to exogenous angiotensin I was 58% +/- 19% with 20 mg lisinopril (mean +/- SD), 58% +/- 11% with 20 mg olmesartan medoxomil, 62% +/- 16% with 40 mg olmesartan medoxomil, and 76% +/- 12% with the highest dose of olmesartan medoxomil (80 mg) (P = .016 versus 20 mg lisinopril and P = .0015 versus 20 mg olmesartan medoxomil). With the combinations, blockade was 80% +/- 22% with 20 mg lisinopril plus 20 mg olmesartan medoxomil and 83% +/- 9% with 20 mg lisinopril plus 40 mg olmesartan medoxomil (P = .3 versus 80 mg olmesartan medoxomil alone). These data demonstrate that a higher dose of the long-acting ARB olmesartan medoxomil can produce an almost complete 24-hour blockade of the blood pressure response to exogenous angiotensin in normal subjects. Hence, a higher dose of a long-acting ARB is as effective as a lower dose of the same compound combined with an angiotensin-converting enzyme inhibitor in terms of blockade of the vascular effects of angiotensin.     

Efficacy of azilsartan medoxomil with chlorthalidone in hypertension

Azilsartan medoxomil (AZL) is the most recently approved angiotensin receptor blocker (ARB) for treating patients with hypertension. A fixed-dose combination product with AZL and the thiazide-like diuretic chlorthalidone (CLD) is now available to treat individuals who require additional blood pressure lowering. For this review, a literature search was conducted using MEDLINE and the keywords and MeSH terms azilsartan, azilsartan medoxomil, chlorthalidone, thiazide, blood pressure and hypertension. References for retrieved articles were also scanned for relevant citations. No language restrictions were used. AZL is structurally related to candesartan and has been shown to provide more potent angiotensin receptor antagonism versus other ARBs. CLD is a thiazide-like diuretic with a longer half-life and greater blood pressure lowering efficacy than hydrochlorothiazide. The combination of AZL plus CLD has superior efficacy to other ARBs alone or in combination with hydrochlorothiazide based on extensive evaluation in clinical trials. This superior efficacy is not offset by a large imbalance in clinically important adverse events.     

Prevention of migraine with olmesartan in patients with hypertension/prehypertension

OBJECTIVE: To explore the effects of olmesartan on frequency and severity of migraine attacks in patients with comorbid hypertension and prehypertension. BACKGROUND: A randomized, double-blind, placebo-controlled, crossover study with a total of 60 patients has demonstrated the efficacy and safety of the angiotensin II receptor blocker candesartan in migraine prophylaxis. We study the potential efficacy and tolerability of olmesartan in preventing migraine in patients with hypertension and prehypertension. DESIGN/METHODS: Twenty-four adults, aged 27 through 76, with either hypertension or prehypertension, were included in this open-label study. Participants suffered from migraines (diagnosed according to International Headache Society classifications) for at least 3 months. Patients were treated with 10 to 40 mg of olmesartan per various observational periods of at least 3 months. Frequency and severity were recorded by office visits or by telephonic interview. RESULTS: Patients reported an 82.5% average reduction in the frequency of migraine attacks. Patients also experienced a 45% average reduction in the severity of migraine attacks measured on a numeric pain scale of 1 to 10. The only undesired effect was dizziness or presyncope. No serious adverse events occurred and no adverse event caused a premature termination. Two patients had no reduction in headache frequency, intensity, and blood pressure. CONCLUSIONS: The favorable results and low rate of adverse effects, in this open migraine prevention study in patients with hypertension or prehypertension, are similar to results of the randomized, double-blind, placebo-controlled, crossover study in patients taking candesartan. Olmesartan shows a potential as an effective and well-tolerated migraine prophylactic agent for patients with comorbid hypertension and prehypertension.     

Blood pressure-lowering efficacy of olmesartan relative to other angiotensin II receptor antagonists: an overview of randomized controlled studies

The aim of the present work was to review published studies investigating the dose-related efficacy on blood pressure (BP) of olmesartan and of other commercially available angiotensin II type I receptor blockers (ARBs). Patient population comprises mild to moderate hypertensive adult patients. We selected studies with comparable design and dose ranges. Dose-effect relationship plots were fitted for diastolic (DBP) and systolic (SBP) BP to the simplified E(max) model. We also examined controlled studies of olmesartan vs. other individual ARBs. Our overview was based on 7280 patients, of which 5769 received an ARB and 1511 received placebo. Except for losartan, the data fitted correctly to the E(max) model, with correlation coefficients ranging from 0.77 to 0.99. BP-lowering efficacy defined as E(max) was superior with olmesartan, (DBP/SBP mmHg: -9.0/-12.4) when compared with candesartan (-6.7/-11.3), irbesartan (-6.5/-11.2) and valsartan (-6.3/-8.9). Head-to-head comparisons of olmesartan to each of the other ARBs used at per-label 'recommended doses', support the finding of a greater BP-lowering effect of olmesartan. This overview suggests that clinically relevant differences in maximal efficacy, as well as in efficacy of per-label recommended doses can be evidenced among individual ARBs. Olmesartan efficacy was consistently at the highest end of the range of efficacy of ARBs studied.     

Cangrelor for treatment of coronary thrombosis

OBJECTIVE: To review and assess available literature on the chemistry, pharmacology, pharmacodynamics, pharmacokinetics, clinical studies, adverse events, drug interactions, special populations, and dosing and administration for cangrelor, a product in late stage Phase II clinical trials. DATA SOURCES: A literature search of MEDLINE (1966-March 2006), International Pharmaceutical Abstracts (1970-February 2006), and Cochrane database (first quarter 2006) was conducted using key terms of cangrelor, AR-C69931MX, and P2Y12 receptor antagonist. Bibliographies of relevant articles were reviewed for additional references. The Medicines Company Web site was reviewed, and a company representative was contacted. STUDY SELECTION AND DATA EXTRACTION: Available English-language literature, including abstracts, preclinical studies, clinical trials, and review articles, was reviewed. DATA SYNTHESIS: Cangrelor is a P2Y12 antagonist under development for treatment of acute coronary syndrome. Cangrelor has been studied as an intravenous infusion in doses of 2 or 4 microg/kg/min. It inhibits platelet aggregation with rapid onset and offset and does not require metabolism for therapeutic activity. Published Phase II trials have demonstrated safety and inhibition of platelet aggregation. CONCLUSIONS: Cangrelor is a promising investigational medication for inhibition of platelet aggregation in acute arterial coronary events. Phase II trials have shown safety and a greater inhibition of platelet aggregation over clopidogrel. Phase III trials will provide more definitive information on clinical efficacy and safety. Until then, the role of cangrelor is uncertain.     

Efficacy and safety of olmesartan medoxomil alone and in combination with hydrochlorothiazide

In at least 50% of patients with hypertension, particularly those with stage 2 hypertension, combination drug therapy is required to achieve the currently recommended blood pressure (BP) goals. It is likely that future hypertension guidelines will recommend lowering BP beyond the currently recommended systolic/diastolic BP goals of lower than 140/90 mmHg for all patients with hypertension and lower than 130/80 mmHg for patients with diabetes or chronic kidney disease. In a series of clinical trials, the combination of olmesartan medoxomil, a well-established angiotensin receptor blocker, and hydrochlorothiazide, a thiazide diuretic, has produced greater reductions in systolic BP and diastolic BP and greater proportions of patients achieving BP goals than monotherapy with either component. Additionally, the increased efficacy resulting from the combination with hydrochlorothiazide does not appear to significantly affect the tolerability profile of olmesartan medoxomil. This article provides a comprehensive evaluation of the chemistry, clinical efficacy, safety and tolerability of this combination and discusses its role in the management of hypertension.     

Effect of the angiotensin II receptor blocker olmesartan on the development of murine acute myocarditis caused by coxsackievirus B3

Ang II (Angiotensin II) has been shown to play a pivotal role in the pathophysiology of various organs, especially the cardiovascular system. The effects of ARBs (Ang II receptor blockers) in the treatment of hypertension, congestive heart failure and myocardial fibrosis have been analysed extensively in human trials, as well as animal models, and the focus of interest is now directed to its pleiotropic effects, especially on inflammatory disorders. To investigate the effects of a new ARB, olmesartan, on immune-mediated myocardial injury, the protective effects of olmesartan on the development of murine acute myocarditis caused by CVB3 (coxsackievirus B3) were analysed. Olmesartan and a non-specific vasodilator hydralazine lowered systolic blood pressure of mice on day 7 after virus inoculation to a similar extent. Olmesartan significantly decreased myocardial inflammation compared with controls, whereas hydralazine significantly increased this. Olmesartan significantly decreased the expression of IFN-gamma (interferon-gamma), FasL (Fas ligand), iNOS (inducible nitric oxide synthase) and PFP (pore-forming protein) in myocardial tissue, indicating that olmesartan suppressed the activation of infiltrating killer lymphocytes. Olmesartan also decreased the expression of CVB3 genomes in myocardial tissue as well as serum levels of 8-OHdG (8-hydroxy-2'-deoxyguanosine), a biomarker of oxidative-stress-induced DNA damage. The findings suggest that olmesartan prevents myocardial damage and may improve the prognosis of patients with acute myocarditis; however, further investigations are needed before clinical use.     

Citalopram in the treatment of depression

OBJECTIVE: To review the efficacy and safety of citalopram in the treatment of depression. DATA SOURCES: MEDLINE search (1966-April 2000), Current Contents search, additional references listed in articles, and unpublished data obtained from the manufacturer were used to identify data from scientific literature. Studies evaluating citalopram (i.e., abstracts, clinical trials, data on file with the manufacturer) were considered for inclusion. STUDY SELECTION: English-language literature was reviewed to evaluate the pharmacology, pharmacokinetics, therapeutic use, and adverse effects of citalopram. DATA EXTRACTION: Controlled animal and human clinical studies published in the English-language literature were reviewed and evaluated. Clinical trials selected for inclusion were limited to those in human subjects and included data from animals if human data were not available. DATA SYNTHESIS: Citalopram is an antidepressant belonging to the class of selective serotonin-reuptake inhibitors (SSRIs) available for the treatment of depression. Citalopram offers therapeutic efficacy similar to that of the other SSRIs and a more favorable adverse effect profile than that of the tricyclic antidepressants (TCAs). Citalopram does not cause anticholinergic or cardiovascular adverse effects associated with the TCAs. Citalopram is the most selective SSRI and, unlike other SSRIs, seems to be relatively free of interaction mediated by the cytochrome P450 system. Citalopram is also the least expensive antidepressant available to date. This review of citalopram includes data from clinical trials comparing safety, tolerability, efficacy, and pharmacoeconomics with TCAs and SSRIs. CONCLUSIONS: Clinical trials demonstrate that citalopram's therapeutic efficacy is significantly greater than that of placebo and is comparable with that of other antidepressants. Citalopram has a favorable adverse effect profile, and thus may be useful in treating depressed patients who cannot tolerate anticholinergic or cardiovascular adverse effects associated with TCAs. It may also be useful in patients with comorbid illnesses requiring concomitant medicines.     

Etoricoxib: a highly selective COX-2 inhibitor

OBJECTIVE: To review the available literature evaluating the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of etoricoxib, a highly selective cyclooxygenase-2 (COX-2) inhibitor that is not currently approved for use in the US. DATA SOURCES: Literature retrieval was accessed through MEDLINE (1966-December 2004), Current Contents (1998-December 2004), and Cochrane Library (4th quarter 2004). References from retrieved articles, information from the manufacturer, and abstracts from the American College of Rheumatology and Annual European Congress of Rheumatology meetings were searched. STUDY SELECTION AND DATA EXTRACTION: All clinical trials published in English evaluating etoricoxib were included in this review. An abstract was excluded if it presented preliminary data from trials that are now published, analyzed data previously reported in a published clinical trial, or compared etoricoxib with placebo for an indication with published active-comparator controlled trials. DATA SYNTHESIS: Twelve clinical trials evaluating efficacy were reviewed. Efficacy for acute pain has been evaluated in acute gout, primary dysmenorrhea, and dental surgery and for chronic pain in rheumatoid arthritis, osteoarthritis, and chronic lower back pain. For safety, 3 clinical trials and 6 retrospective analyses of gastrointestinal, renovascular, or cardiovascular adverse effects were reviewed. CONCLUSIONS: Available studies demonstrate the efficacy of etoricoxib compared with nonsteroidal antiinflammatory drugs, but no published studies to date have compared etoricoxib with other selective COX-2 inhibitors. While these agents have demonstrated a significant reduction in gastrointestinal adverse effects, the cardiovascular adverse effects of selective COX-2 inhibition are not well defined. Further study is necessary to delineate the benefits and risks of etoricoxib compared with alternative treatment regimens.     

Parecoxib for parenteral analgesia in postsurgical patients

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy and safety studies, adverse effects, drug interactions, and dosage and administration of parecoxib sodium, a selective cyclooxygenase-2 (COX-2) inhibitor. DATA SOURCES: Information was obtained from MEDLINE searches of the English-language literature (1996-May 2003). Search terms included parecoxib, parecoxib sodium, SC-69124A, and selective cyclooxygenase-2 inhibitor. STUDY SELECTION AND DATA EXTRACTION: We reviewed available literature, which included abstracts, clinical trials, and data on file with the manufacturer. DATA SYNTHESIS: Parecoxib sodium is a novel selective COX-2 inhibitor under development for parenteral administration. It has produced efficacious analgesia following dental, gynecologic, and orthopedic surgery. The adverse effect profile has been compared with that of ketorolac; no statistically significant differences were identified. There are no documented drug interactions when parecoxib is coadministered with midazolam, propofol, or unfractionated heparin. CONCLUSIONS: Parecoxib sodium is in the final stages of Phase III trials and has a favorable safety and efficacy profile. Its place in moderate to severe postsurgical pain management will be further defined when more pharmacoeconomic and postmarketing safety data are available. Theoretical benefits are its lower potential for gastrointestinal adverse effects compared with ketorolac and lower opioid requirements after surgery.     

Atypical antipsychotics: Part II: Adverse effects, drug interactions, and costs

OBJECTIVE: To compare the adverse effects, drug interactions, and costs of conventional and atypical agents, and to provide a summary of therapeutic guidelines. Part I compared the pharmacology, pharmacokinetics, and efficacy of atypical and conventional agents. DATA SOURCES: Information was retrieved from a MEDLINE English-language literature search from June 1986 to June 1998 and by review of references. Indexing terms included atypical antipsychotics, neuroleptics, clozapine, risperidone, olanzapine, sertindole, quetiapine, and ziprasidone. STUDY SELECTION: Comparative studies were selected when possible; placebo-controlled studies were included when data were limited on newer atypical antipsychotics. DATA EXTRACTION: Emphasis was placed on properly designed clinical trials that assessed dosage, expanded efficacy, enhanced adverse effect profile, and cost. DATA SYNTHESIS: Significant adverse effects are agranulocytosis with clozapine, dose-dependent extrapyramidal side effects (EPS) with risperidone, and neuroleptic malignant syndrome with clozapine and risperidone. Clinically relevant drug interactions may occur with clozapine-lorazepam, clozapine-fluvoxamine, and sertindole-quinidine. Newer atypical agents have high acquisition costs but may reduce noncompliance and rehospitalization rates. CONCLUSIONS: Risperidone or olanzapine are recommended as first-line agents for schizophrenia due to accumulating controlled trials and clinical experience. Quetiapine should be considered with partial response or if EPS develop, and clozapine is an option with treatment-refractory patients. Atypical agents may contribute to a better quality of life, but conventional neuroleptics are the first choice for strictly cost considerations.     

Treatment options for rheumatoid arthritis: celecoxib, leflunomide, etanercept, and infliximab

OBJECTIVE: To review new pharmacologic agents approved for use in the management of rheumatoid arthritis (RA). DATA SOURCES: A MEDLINE search (1966-January 2000) was conducted to identify English-language literature available on the pharmacotherapy of RA, focusing on celecoxib, leflunomide, etanercept, and infliximab. These articles, relevant abstracts, and data provided by the manufacturers were used to collect pertinent data. STUDY SELECTION: All controlled and uncontrolled trials were reviewed. DATA EXTRACTION: Agents were reviewed with regard to mechanism of action, efficacy, drug interactions, pharmacokinetics, dosing, precautions/contraindications, adverse effects, and cost. DATA SYNTHESIS: Traditional pharmacologic treatments for RA have been limited by toxicity, loss of efficacy, or both. Increasing discoveries into the mechanisms of inflammation in RA have led to the development of new agents in hopes of addressing these limitations. With the development of celecoxib, a selective cyclooxygenase-2 inhibitor, the potential exists to minimize the gastrotoxicity associated with nonsteroidal antiinflammatory drugs. Leflunomide has been shown to be equal to or less efficacious than methotrexate, and may be beneficial as a second-line disease-modifying antirheumatic drug (DMARD). The biologic response modifiers, etanercept and infliximab, are alternatives that have shown benefit alone or in combination with methotrexate. However, they should be reserved for patients who fail to respond to DMARD therapy. Further studies should be conducted to evaluate the long-term safety and efficacy of these agents as well as their role in combination therapy. CONCLUSIONS: Celecoxib, leflunomide, etanercept, and infliximab are the newest agents approved for RA. Clinical trials have shown that these agents are beneficial in the treatment of RA; however, long-term safety and efficacy data are lacking.     

Amlodipine besylate/olmesartan medoximil fixed combination for the treatment of hypertension

National and international guidelines recommend the use of combination drugs as a first-line therapy for persons with stage 2 hypertension (blood pressure >160/100 mmHg). Although hypertension is common (30% of adults in the USA), its control to recommended blood pressure levels of under 140/90 mmHg remains low, at 36.8%. In the past, fixed-drug combinations included a diuretic with another antihypertensive drug. Recently, combinations of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers mostly with dihydropyridine calcium channel blockers have been developed and approved for the treatment of hypertension. One of these, olmesartan medoxomil in combination with amlodipine besylate has been shown to be effective and safe for the treatment of hypertension. In a large, randomized, placebo-controlled study (Combination of Olmesartan medoxomil and Amlodipine besylate in Controlling High blood pressure [COACH]) of 1940 patients, the high-dose combinations of olmesartan medoxomil and amlodipine besylate 40/10 mg/day reduced the sitting systolic and diastolic blood pressure by 29/19 mmHg from baseline (p < 0.001) and resulted in 54% of patients achieving blood pressure goals. It also decreased the pedal edema induced by amlodipine monotherapy 10 mg/day by 36.1%. This drug combination, besides being effective, is also safe and well tolerated.     

Combined therapy with an angiotensin II receptor blocker and an angiotensin-converting enzyme inhibitor in heart failure

OBJECTIVE: To evaluate the safety, tolerability, and efficacy of chronic combination therapy with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) in the management of heart failure. DATA SOURCES: Clinical literature was accessed through MEDLINE (January 1966-June 2000). Key search terms included angiotensin-converting enzyme inhibitor; losartan; combined modality therapy; drug effects; heart failure, congestive; and receptors, angiotensin. DATA SYNTHESIS: Heart failure is widely prevalent and continues to be associated with high morbidity and mortality, even with currently recommended care. At the moderate doses studied for patients with mild heart failure in brief trials, combined ACE inhibitor and ARB therapy was well tolerated and had an additive effect in reducing blood pressure and relieving symptoms of heart failure. CONCLUSIONS: An ARB combined with an ACE inhibitor may benefit heart failure patients who are receiving all other recommended therapies. Further trials are needed to evaluate long-term safety effectiveness, quality of life, and survival before the combination can be recommended for routine use.     

Angiotensin II receptor blockers in patients with ACE inhibitor-induced angioedema

OBJECTIVE: To determine the safety of using angiotensin II receptor blockers in patients who have experienced angioedema following treatment with angiotensin-converting enzyme (ACE) inhibitors. DATA SOURCES: Clinical literature identified through MEDLINE (January 1966-August 1999). Key search terms included angioneurotic edema, angiotensin-converting enzyme inhibitors, receptors-angiotensin, and losartan. DATA SYNTHESIS: ACE inhibitor-induced angioedema occurs with an incidence of 0.1-0.5%. Alternative therapy is necessary for patients who experience this potentially life-threatening adverse effect. Since angiotensin II receptor blockers do not increase concentrations of bradykinin, the proposed mechanism of ACE inhibitor-induced angioedema, they were presumed to be safe alternatives. Recent case reports, however, document angioedema following therapy with angiotensin II receptor blockers; 32% of the reported patients experienced a prior episode of angioedema attributed to ACE inhibitor therapy. CONCLUSIONS: Until the exact cause of both ACE inhibitor- and angiotensin II receptor blocker-induced angioedema is determined, angiotensin II receptor blockers should be used with extreme caution in patients with a prior history of angioedema.