Imipenem monotherapy versus combination therapy in the management of mixed bacterial infection: a critical appraisal

There has been a great deal of interest in the use of imipenem monotherapy rather than combinations of antimicrobials for mixed bacterial infections. A review of the published comparative studies of imipenem versus combinations in serious mixed bacterial infections indicated that, overall, imipenem is at least as effective as, and maybe less expensive than, the combinations tested. Several studies suggest that clinical response to imipenem is more rapid than to the comparison regimens; however, other factors may have influenced these values, and the numbers of patients in these reports were small. Imipenem is devoid of the adverse effects associated with aminoglycosides. Other adverse effects, including superinfection and central nervous system toxicity, were similar for imipenem and the comparison regimens. Meta-analysis of the published reports and abstracts revealed that imipenem is as effective as combination regimens for the treatment of serious mixed bacterial infection.     

Paclitaxel: a pharmacoeconomic review of its use in non-small cell lung cancer.

A number of first-line chemotherapy options for patients with advanced non-small cell lung cancer (NSCLC) are advocated in treatment guidelines and/or by various clinical investigators. Platinum-based chemotherapy has clearly demonstrated efficacy in patients with advanced NSCLC and is generally recommended as first-line therapy, although there is increasing interest in the use of non-platinum chemotherapy regimens. Among the platinum-based combinations currently used in clinical practice are regimens such as cisplatin or carboplatin combined with paclitaxel, vinorelbine, gemcitabine, docetaxel or irinotecan. The particular combinations employed may vary between institutions and geographical regions. Several pharmacoeconomic analyses have been conducted on paclitaxel in NSCLC and most have focused on its use in combination with cisplatin. In terms of clinical efficacy, paclitaxel-cisplatin combinations achieved significantly higher response rates than teniposide plus cisplatin or etoposide plus cisplatin (previously thought to be among the more effective regimens available) in two large randomised trials. One of these studies showed a survival advantage for paclitaxel plus cisplatin [with or without a granulocyte colony-stimulating factor (G-CSF)] compared with etoposide plus cisplatin. A Canadian cost-effectiveness analysis incorporated data from one of the large randomised comparative trials and showed that the incremental cost per life-year saved for outpatient administration of paclitaxel plus cisplatin versus etoposide plus cisplatin was $US 22181 (30619 Canadian dollars; $Can) [1997 costs]. A European analysis incorporated data from the other large randomised study and showed slightly higher costs per responder for paclitaxel plus cisplatin than for teniposide plus cisplatin in The Netherlands ($US 30769 vs $US 29592) and Spain ($US 19 923 vs $US 19724) but lower costs per responder in Belgium ($US 22852 vs $US 25000) and France ($US28 080 vs $US 34747) [1995/96 costs]. In other cost-effectiveness analyses, paclitaxel plus cisplatin was associated with a cost per life-year saved relative to best supportive care of approximately $US 10000 in a US study (year of costing not reported) or $US 11200 in a Canadian analysis ($Can 15400; 1995 costs). Results were less favourable when combining paclitaxel with carboplatin instead of cisplatin and particularly when G-CSF was added to paclitaxel plus cisplatin. The Canadian study incorporated the concept of extended dominance in a threshold analysis and ranked paclitaxel plus cisplatin first among several comparator regimens (including vinorelbine plus cisplatin) when the threshold level was $Can 75000 ($US 54526) per life-year saved or per quality-adjusted life-year gained (1995 values). CONCLUSION: Current treatment guidelines for advanced NSCLC recognise paclitaxel-platinum combinations as one of the first-line chemotherapy treatment options. In two large head-to-head comparative clinical trials, paclitaxel plus cisplatin was associated with significantly greater response rates than cisplatin in combination with either teniposide or etoposide, and a survival advantage was shown for paclitaxel plus cisplatin (with or without G-CSF) over etoposide plus cisplatin. There are limitations to the currently available pharmacoeconomic data and further economic analyses of paclitaxel-carboplatin regimens are warranted, as this combination is widely used in NSCLC and appears to have some clinical advantages over paclitaxel plus cisplatin in terms of ease of administration and tolerability profile. Nevertheless, results of various cost-effectiveness studies support the use of paclitaxel-platinum combinations, particularly paclitaxel plus cisplatin, as a first-line chemotherapy treatment option in patients with advanced NSCLC.     

Cost effectiveness of cholinesterase inhibitors in the treatment of Alzheimer's disease: a review with methodological considerations

Cholinesterase inhibitors have been available for the treatment of Alzheimer's disease since 1993. They have significantly positive effects on cognitive functioning and other domains of functional capacity, such as activities of daily life in terms of efficacy, but the clinical value of these effects are under discussion. Cholinesterase inhibitors may also influence behavioural and psychological symptoms in Alzheimer's disease. Cholinesterase inhibitors are also regarded as rather expensive and, therefore, the question of cost effectiveness is essential. Pharmacoeconomic evaluations of cholinesterase inhibitors have so far been conducted in retrospect on efficacy data from prospective randomised clinical trials combined with economic data from other sources. There are no published specific cost-effectiveness studies of cholinesterase inhibitors which prospectively collected empirical data on costs and outcomes. There is only one published randomised clinical trial with such empirical data with a cost consequence analysis design, indicating cost neutrality. Several types of models to describe the long-term effects have been published, indicating cost effectiveness. However, due to methodological considerations, the validity of these models is difficult to judge. A research agenda for the cost effectiveness of cholinesterase inhibitors is proposed, including long-term studies with empirical data on resource use, costs and outcomes, studies on quality of life, informal care and behavioural and psychological symptoms, combination and comparative studies on mild cognitive impairment.     

Multidrug-resistant Acinetobacter baumannii infections: Current evidence on treatment options and the role of pharmacokinetics/pharmacodynamics in dose optimisation

Acinetobacter baumannii remains a difficult-to-treat pathogen that poses a significant challenge to clinicians and costs to the healthcare system. There is a lack of clinical efficacy data to aid in the selection of optimal treatment for multidrug-resistant (MDR) A. baumannii infections. This paper aimed to review recent literature on the treatment of MDR A. baumannii infections and novel agents in the pipeline and to discuss the clinical data supporting their use. Colistin has been widely studied as monotherapy or as part of combination therapy, but its use is limited due to nephrotoxicity. The clinical benefit of combination therapy, whether empirical or targeted, has yet to be demonstrated owing to a lack of definitive evidence from randomised controlled trials (RCTs). Most available clinical studies are retrospective and lack control groups, which offers low-grade evidence. Novel agents such as cefiderocol, plazomicin, eravacycline and sulbactam/ETX2514 combination are promising options for the treatment of different infectious pathologies caused by MDR A. baumannii, but these have yet to be evaluated in RCTs. A better understanding of the pharmacokinetics/pharmacodynamics of the ‘old’ antibiotics is required to optimise their dosing regimens in order to maximise bacterial killing, minimise toxicities and improve clinical outcomes.     

Merging the cognitive behavioral and psychopharmacological paradigms in comparative studies: controversies,issues, and some solutions

In the past, many studies attempting to compare pharmacological and psychosocial treatments for mood and anxiety disorders have been conducted by partisans of either approach. More recently, rigorously conducted, unbiased comparative studies have begun to appear. Here we reviewed our own experience in designing and conducting a multicenter study comparing medication and cognitive behavioral therapy and their combination for the treatment of panic disorder.     

Comparative evaluation of the Cockcroft-Gault Equation and the Modification of Diet in Renal Disease (MDRD) study equation for drug dosing: an opinion of the Nephrology Practice and Research Network of the American College of Clinical Pharmacy

Accurate assessment of kidney function is an important component of determining appropriate drug dosing regimens. Nearly all manufacturer-recommended dosage adjustments are based on creatinine clearance ranges derived from clinical pharmacokinetic studies performed during the drug development process. The Cockcroft-Gault (CG) equation provides an estimate of creatinine clearance and is the equation most commonly used to determine drug dosages in patients with impaired kidney function. The Modification of Diet in Renal Disease (MDRD) study equation has also been proposed for this purpose. Published studies report that drug dosages determined by the two equations do not agree in 10-40% of cases. However, interpretation and comparison of these studies are complicated by the variable creatinine methods used for calculating CG and MDRD estimates, the patient populations studied, and a lack of outcomes data demonstrating the clinical significance of dosing discrepancies. Moreover, the impact of reporting standardized serum creatinine values on the accuracy of the CG equation and corresponding drug dosing regimens have been questioned. Currently, no prospective pharmacokinetic studies have been conducted with use of the MDRD equation to generate dosing recommendations, and limited data are available to support its use in some patient populations representing demographic extremes. Collectively, these issues have resulted in considerable confusion among clinicians and have fueled a healthy debate on whether or not to use the MDRD equation to determine drug dosages. Each of these issues is reviewed, and a proposed algorithm for using creatinine-based kidney function assessments in drug dosing is provided. Knowledge of the advantages, limitations, and clinical role of each equation will facilitate their safe and effective use in drug dosing.     

Polyethylene glycol-liposomal doxorubicin: a review of its use in the management of solid and haematological malignancies and AIDS-related Kaposi's sarcoma

Polyethylene glycol (PEG)-liposomal doxorubicin is a formulation of the anthracycline doxorubicin in which the drug is encapsulated in PEG-coated liposomes. This alters the pharmacokinetic properties of doxorubicin, prolonging circulation time and enhancing localisation to tumours. In a large randomised trial, intravenous PEG-liposomal doxorubicin was at least as effective as topotecan in patients with ovarian cancer refractory or sensitive to first-line platinum-based chemotherapy. Overall response rates of patients with ovarian cancer refractory to platinum- and paclitaxel-based chemotherapy who received the drug ranged from 18.3 to 27.6% in noncomparative clinical trials. PEG-liposomal doxorubicin also has antitumour activity in patients with metastatic breast cancer pretreated with other chemotherapeutic agents. Overall response rates were similar in patients with pretreated metastatic breast cancer who had received PEG-liposomal doxorubicin or two comparator salvage chemotherapy regimens (vinorelbine or mitomycin C plus vinblastine) in an interim analysis of a large randomised study. In patients with advanced AIDS-related Kaposi's sarcoma, PEG-liposomal doxorubicin monotherapy produced overall response rates ranging from 46 to 77% in randomised trials. The drug was significantly more effective than bleomycin plus vincristine alone or in combination with standard doxorubicin, as measured by tumour response. As a replacement for standard doxorubicin in commonly used combination therapies, PEG-liposomal doxorubicin has shown activity in multiple myeloma and aggressive non-Hodgkin's lymphoma in small, preliminary trials. The most common adverse events associated with PEG-liposomal doxorubicin are myelosuppression, palmar-plantar erythrodysaesthesia, stomatitis and nausea. These can be managed by delaying or reducing dosages. Although preliminary trials are promising, the relative cardiotoxicity of PEG-liposomal doxorubicin compared with the standard formulation has not been clearly established. CONCLUSIONS: Monotherapy with PEG-liposomal doxorubicin is effective as a second-line chemotherapy in patients with platinum-refractory ovarian cancer and in patients with metastatic breast cancer. However, as with all chemotherapeutic agents, the benefits of treatment need to be weighed against the agent's tolerability profile. Strong comparative data have helped to establish PEG-liposomal doxorubicin as the first-line treatment option in patients with advanced Kaposi's sarcoma. Anticancer activity has also been observed in studies conducted in small numbers of patients with multiple myeloma or non-Hodgkin's lymphoma receiving PEG-liposomal doxorubicin instead of standard doxorubicin in combination regimens, although further data are needed to confirm the clinical relevance of these findings.     

Management of opioid-induced gastrointestinal effects in patients receiving palliative care

Opioid-induced gastrointestinal side effects, namely, nausea and constipation, are bothersome yet often easy to manage. Due to their widespread frequency, it is imperative that prophylactic and treatment modalities be understood. Although many pharmacotherapeutic agents are available with which to prevent or treat these side effects, few randomized, placebo-controlled studies have been conducted in terminally ill patients, thus limiting most treatment decisions to empiric therapies based on extrapolated data. A strong understanding of the pathophysiology of the sequelae is therefore paramount. Common agents administered for nausea are butyrophenones, phenothiazines, metoclopramide, and serotonin-receptor antagonists. Those given to manage constipation are stimulant laxatives and stool softeners, individually or in combination.     

A chart review comparing paregoric to methadone in the treatment of neonatal opioid withdrawal

Neonatal opioid withdrawal often requires treatment but there have been few recent studies of current pharmacological interventions to guide treatment. This retrospective chart review provides an exploratory examination of newborns treated with either methadone or paregoric for opioid withdrawal and outlines dosage ranges and intervals, side effects, and clinical outcomes of the two regimens. The outcome variables examined were time to resolution of withdrawal symptoms, rate of decrease in symptom severity, and length of hospital stay. There were no observed differences in outcome variables between the two treatment groups and side effect profiles were similar. Dosages, dosage intervals, and tapering regimens were consistent with American Academy of Pediatrics recommendations. Although the sample size is small and standardized regimens were not used, this study provides preliminary data about dosing levels and dosing intervals of these two pharmacologic treatment agents. Both groups of infants had favorable outcomes, although given the variation in treatment regimens it is difficult to draw an equation of equivalency. These results are applicable to the design of future studies of pharmacological interventions.     

An update on the safety of amlodipine

A previous article on the safety of amlodipine reviewed data from over 4,000 subjects who participated in clinical trials sponsored by Pfizer Central Research. Once-daily amlodipine was shown to be a well-tolerated treatment of hypertension and myocardial ischemia. Although amlodipine is a potent vasodilator, there was a low incidence of side effects such as headache, flushing, and dizziness. Amlodipine was not associated with adverse effects on hematologic or biochemical safety parameters nor on serum cholesterol or triglyceride levels. Amlodipine did not alter electrical conduction in the heart. Amlodipine had a favorable safety profile in comparative trials vs. beta-blockers. The data base of comparative trials vs. other calcium antagonists was small but the toleration of amlodipine was similar to that of verapamil and diltiazem. No data from comparative trials vs. another calcium antagonist of the dihydropyridine class have been available. This article reviews data from recently completed trials vs. nitrendipine and from trials in which amlodipine was used in combination with other agents. Amlodipine was better tolerated than nitrendipine and had a much lower incidence of side effects usually related to vasodilatation. This difference in side-effect profile was especially marked during the first days of treatment. Amlodipine was well tolerated when used in combination with beta-blockers, diuretics, ACE inhibitors, and nitrates. The gradual onset of action and relatively long half-life of amlodipine are the probable cause for the improved toleration in comparison with other dihydropyridines. Besides the low incidence of trivial side effects, increasing clinical experience with amlodipine provides no evidence that amlodipine is a cause of rare but serious adverse effects. It is concluded that amlodipine is an antihypertensive and anti-ischemic agent that has the combined advantages of a good safety profile with once-daily dosage and a smooth onset and long duration of action.     

Saquinavir-soft gel: establishing saquinavir in HAART regimens

The initial formulation of the HIV protease inhibitor (PI) saquinavir (SQV) in hard gel capsules (Invirase) demonstrated significant clinical benefit in double and triple combination regimens in comparative studies. However, pharmacological limitations of this preparation resulted in fewer patients achieving optimal treatment responses than observed with other PIs. Changes in formulation and dosing to a new soft gelatin capsule formulation of SQV (SQV-SGC, Fortovase result in an average 8-fold increase in SQV exposure with SQV-SGC. Data from clinical trials indicate that this enhanced plasma exposure translates into more potent antiviral activity, with small comparative studies suggesting activity to be similar to other available PIs in triple therapy highly-active antiretroviral therapy (HAART) regimens. Additionally, SQV-SGC appears to be an excellent candidate for PI combination use. SQV-SGC appears well-tolerated with a low incidence of mainly gastrointestinal side-effects. The lower affinity to P450 isozymes of SQV means that the incidence of drug interactions is low, indeed probably lower than with other approved members of this class. Current obstacles to SQV-SGC's widespread use include only limited, short-term bid dosing data (outside of combination with ritonavir) and the pill burden of 18 capsules per day.     

Cost considerations in the treatment of colorectal cancer

Colorectal cancer is among the most common malignancies in developed countries. Screening can reduce mortality significantly, although the most appropriate method is still under debate. Observational studies have revealed that lifestyle measures may also be beneficial for prevention of colorectal cancer. Surgery is still the most effective treatment modality for colorectal cancer. The survival benefits of chemotherapy are only modest. For nearly 5 decades, 5-fluorouracil (5-FU) has been the main cytotoxic agent for treatment of colorectal cancer. In the last decade, the new cytotoxic agents raltitrexed, irinotecan and oxaliplatin have been introduced, next to the oral 5-FU analogues capecitabine and tegafur in combination with uracil (UFT). Moreover, the immunotherapeutics bevacizumab and cetuximab have become approved for treatment of metastatic colorectal cancer. The economic implications of colorectal cancer treatment are substantial. The costs of treatment are mainly attributable to the early and terminal stage of the disease (i.e. surgery, hospitalisation, chemo- and immunotherapy and supportive care). The introduction of new chemo- and immunotherapeutics has caused a continuing increase of treatment expenditures. Therefore, comparative costs and cost effectiveness are important for assessing the value of new treatment regimens. The available study results suggest that addition of irinotecan or oxaliplatin to 5-FU/folinic acid dosage regimens is cost effective. Also, capecitabine is calculated to be cost effective when compared with 5-FU/folinic acid. For UFT, no comparative studies of cost effectiveness were found. Since raltitrexed and 5-FU/folinic acid have shown equal efficacy in terms of survival, cost-effectiveness analysis is considered not to be applicable and cost-minimisation analysis may be sufficient. At present, pharmacoeconomic analyses of combination treatment with the immunotherapeutics bevacizumab or cetuximab are not available, except for recent cost-effectiveness considerations by the UK National Institute for Health and Clinical Excellence with negative recommendations for both agents in the treatment of metastatic colorectal cancer. Given the high treatment costs, substantial toxicity and relatively limited efficacy of the fast changing chemo- and immunotherapeutic combinations for colorectal cancer, examination of cost-effectiveness studies should be conducted on a routine basis along with determination of clinical benefits.     

Photorejuvenation of facial skin with topical 20% 5-aminolevulinic acid and intense pulsed light treatment: a split-face comparison study

BACKGROUND: Photorejuvenation of facial skin has been reported after intense pulsed light (IPL) therapy alone and in conjunction with topical 5-aminolevulinic acid (5-ALA), but no comparative studies between these regimens have been performed. OBJECTIVE: To evaluate the safety and effectiveness of combination topical 5-ALA and IPL compared to IPL treatment alone. METHODS: Ten patients with mild to moderate photodamage were randomly assigned treatment with 5-ALA + IPL on one facial half and IPL alone on the contralateral side. Two treatments were delivered at 4-week intervals. Clinical improvement scores were determined by masked evaluations of digital photographs obtained at baseline, prior to each treatment session, and at 1, 3, and 6 months after the final treatment. RESULTS: Higher clinical improvement scores were noted on the combination 5-ALA + IPL treated areas. Mild edema, erythema, and desquamation were observed on the facial halves where 5-ALA was applied. No scarring or unwanted pigmentary alteration was seen. CONCLUSIONS: Photodynamic therapy with combination topical 5-ALA + IPL is safe and more effective for facial rejuvenation than IPL treatment alone.     

Ciprofloxacin/metronidazole versus beta-lactam-based treatment of intra-abdominal infections: a meta-analysis of comparative trials

Intra-abdominal infections are polymicrobial and result in substantial morbidity and mortality. The combination of ciprofloxacin/metronidazole as well as several beta-lactam-based regimens are among the commonly used regimens for the treatment of patients with such infections. Thus, we sought to review the evidence from available comparative clinical trials studying ciprofloxacin/metronidazole versus broad-spectrum beta-lactam-based regimens in the treatment of intra-abdominal infections. Studies for the meta-analysis were retrieved from searches of the PubMed database. Five available comparative trials (four randomised controlled trials and one non-randomised comparative trial) including 1431 patients with intra-abdominal infections were included in the meta-analysis. There was a statistically significant difference between the compared arms with regard to cure in favour of the ciprofloxacin/metronidazole combination (odds ratio (OR)=1.69, 95% confidence interval (CI) 1.20-2.39). There was no statistically significant difference between the compared arms with regard to total mortality (OR=1.10, 95% CI 0.71-1.69), mortality attributable to infection (OR=1.42, 95% CI 0.66-3.06) and toxicity (OR=1.25, 95% CI 0.66-2.35). In conclusion, pooled data from the available comparative trials suggest that the ciprofloxacin/metronidazole combination may be superior to beta-lactam-based therapeutic regimens in the treatment of intra-abdominal infections with regard to cure of infections, although no difference in mortality was found.     

Pharmacoeconomic analysis of empirical therapy with ceftazidime alone or combination antibiotics for febrile neutropenia in cancer patients

There is evidence to suggest that single-agent broad spectrum antibacterials may be cost-effective alternatives to combination antibiotics for the empirical management of febrile neutropenia in cancer patients. The objectives of the present study were 2-fold. The first objective was to compare the clinical effectiveness of ceftazidime monotherapy with that of 2 combination antibiotic regimens in cancer patients with febrile neutropenia. The 2 comparator regimens consisted of tobramycin plus piperacillin, either with (regimen 'CAP') or without (regimen 'AP') cefazolin. The second objective was to perform a cost-effectiveness analysis of the 3 regimens. Meta-analysis of randomised comparative trials between the 3 therapy groups was performed to determine the average overall response rate after 3 to 5 days of treatment. Seven clinical studies were selected for analysis. The overall incidence of adverse drug reactions (ADRs) was determined using the results of comparative and noncomparative studies. A comparative cost-analytic model was applied from a hospital perspective. The costs of primary therapy, hospitalisation, laboratory tests, routine patient care and treating ADRs were calculated, as were future costs. Monotherapy with ceftazidime was associated with an overall response rate of 63.5% and mean per-patient costs of $Can12,000 to $Can14,000. In comparison, regimen AP was associated with an overall response rate of 58.8% and mean costs of $Can13,000 to $Can16,000 per patient. The overall response rate in patients receiving CAP was 75.3%, and the mean cost per patient was $Can11,000 to $Can12,000. Thus, regimen CAP was the most cost-effective therapy from a hospital perspective.     

替加环素单药与联合方案治疗多重耐药菌感染疗效对比的系统评价#br#

目的 替加环素是一种广谱的新型四环素类抗生素,长期单独使用可能存在耐药菌出现增多的问题。本文将系统性评价以替加环素为基础的联合治疗方案与替加环素单药方案治疗多重耐药菌感染疗效的对比。方法 通过检索PubMed、Embase、the Cochrane Library、CNKI、维普、万方等数据库及手工检索会议论文,寻找有关替加环素单药和联合治疗方案比较的随机对照研究、队列研究、病例丛和个案报道。检索日期截止到2016年12月31日。英文数据库的检索词为“tigecycline”、“tygacil”、“monotherapy”以及“combination”。中文数据库的检索词为“替加环素”、“单药”及“联合”。相关综述研究也一并手工检索。结果 仅1篇符合筛选条件的相关RCT研究。最终纳入9项对比研究(含1510个事件)和22项非对比性研究(含26个事件)。对比研究显示基于替加环素的联合治疗方案与替加环素单药治疗方案相比疗效上无显著差异。然而26例个案报道中23例显示替加环素联合的治疗方案临床效果会更佳。此外,研究还显示,与替加环素组合的治疗方案中最常见的抗菌药物是多黏菌素、碳青霉烯类、氨基糖苷类和氟喹诺酮类。结论 替加环素为基础的联合方案似乎更优于单药方案,常见有效的联合药物为多黏菌素、碳青霉烯类、氨基糖苷类和氟喹诺酮类。未来需要进行更多的前瞻性、随机对照、双盲研究来探索联合治疗方案和单药治疗方案疗效对比以及何种药物与替加环素的联合会更适宜。     

The pharmacologic management of the syndrome of inappropriate secretion of antidiuretic hormone

There have been numerous treatment modalities reported in the literature concerning the acute and chronic treatment of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Water restriction remains the mainstay of therapy. However, patient noncompliance for this regimen often makes additional treatment modalities necessary. In the long-term treatment of chronic SIADH, lithium, demeclocycline, loop diuretics, and urea are helpful, regardless of the origin of the SIADH. The use of lithium is not recommended due to the incidence of digestive, cardiac, thyroid, and central nervous system side effects, as well as the demonstrated superiority of demeclocycline. Urea and loop diuretics, although shown to be effective, have not been used clinically to the extent as demeclocyline, and are not free of adverse effects. Phenytoin is limited in its use to the treatment of SIADH secondary to abnormalities of the hypothalamic-pituitary axis, and plays no role in the treatment of tumor-induced SIADH. Demeclocyline has been shown to be effective in all types of SIADH. The lack of comparative studies of long-term treatment regimens makes the selection of a regimen of choice difficult. At this point loop diuretics or demeclocycline appear to be the regimens of choice based primarily upon case reports and relatively small comparative study patient populations. Further comparative studies are needed in an attempt to identify the most efficacious regimen with the minimal incidence of adverse effects.     

Comparison of angiotensin II type 1 receptor antagonists in the treatment of essential hypertension

Hypertension is a major health problem worldwide, yet remains under-diagnosed and under-treated. Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) are highly effective at reducing blood pressure (BP), exhibit renoprotective properties and have placebo-like tolerability. However, it is unclear whether there are clinical differences in efficacy and tolerability between the available ARBs. A review of published, randomized, comparative clinical trials suggests that differences in BP-lowering efficacy and 24-hour BP control may exist between ARBs, although it appears that there is no evidence for important differences in tolerability between ARBs. Few studies have assessed attainment rates for important combined systolic BP (SBP)/diastolic BP (DBP) goals recommended in treatment guidelines. Likewise, few studies have directly compared more than two agents or ARB/hydrochlorothiazide fixed-dose combinations, and most ARBs have not been compared across their full recommended dosage ranges. Overall, there is insufficient weight of evidence to allow definitive conclusions to be drawn regarding the comparative efficacy of the available ARBs. However, newer ARBs (e.g. olmesartan medoxomil and telmisartan) appear to be more effective than older ARBs (e.g. losartan and valsartan) in reducing DBP and/or SBP in some trials. In addition, olmesartan medoxomil treatment regimens resulted in high BP control rates in several trials, but head-to-head trials with other ARBs are required to put these control rates into perspective, especially for SBP control with various agents. The purpose of this review is to present published data from ARB efficacy trials for a comparison of various efficacy parameters among the agents within this drug class.     

Toward understanding genetic risk for differential antipsychotic response in individuals with schizophrenia

Antipsychotic treatment response is highly heterogeneous and unpredictable in terms of both efficacy and side effects. A combination of factors influences treatment outcome, including clinical, demographic, environmental and genetic factors. No comprehensive studies have quantified the relative contributions of these factors to date. Two decades of pharmacogenetic and pharmacogenomic studies have attempted to identify key gene variants associated with antipsychotic response, with a dual goal of better understanding the mechanisms underlying drug response and guiding prescribing decisions in clinical care. Pharmacogenetic studies have succeeded in identifying several genes that are associated with antipsychotic treatment efficacy or side effects. However, the strength of these associations is modest and they are of limited clinical value. Genome-wide association studies, moving beyond hypothesis-based discovery, have greater potential to identify novel gene associations, although only a few genome-wide association studies have been conducted and they have not revealed clearly significant findings. The first pharmacogenetic tests to guide the selection or dosing of antipsychotic drugs are now commercially available. Their uptake has been limited by the modest level of prediction they offer, compounded by the lack of data supporting their clinical or economic benefits. Advances in genomic analysis techniques, the better characterization of larger subject cohorts and an improved understanding of the role of environmental factors and gene-environment interactions are renewing hope that future research will identify genetic variants with stronger associations with treatment outcome. Tests incorporating such genetic data, with environmental and clinical variables, may offer the potential to personalize medicine and significantly improve the efficacy and tolerability of antipsychotic treatment.