Lack Of Clinical Efficacy Research Articles

Clinical review: Exogenous surfactant therapy for acute lung injury/acute respiratory distress syndrome--where do we go from here?

Acute lung injury and acute respiratory distress syndrome (ARDS) are characterised by severe hypoxemic respiratory failure and poor lung compliance. Despite advances in clinical management, morbidity and mortality remains high. Supportive measures including protective lung ventilation confer a survival advantage in patients with ARDS, but management is otherwise limited by the lack of effective pharmacological therapies. Surfactant dysfunction with quantitative and qualitative abnormalities of both phospholipids and proteins are characteristic of patients with ARDS. Exogenous surfactant replacement in animal models of ARDS and neonatal respiratory distress syndrome shows consistent improvements in gas exchange and survival. However, whilst some adult studies have shown improved oxygenation, no survival benefit has been demonstrated to date. This lack of clinical efficacy may be related to disease heterogeneity (where treatment responders may be obscured by nonresponders), limited understanding of surfactant biology in patients or an absence of therapeutic effect in this population. Crucially, the mechanism of lung injury in neonates is different from that in ARDS: surfactant inhibition by plasma constituents is a typical feature of ARDS, whereas the primary pathology in neonates is the deficiency of surfactant material due to reduced synthesis. Absence of phenotypic characterisation of patients, the lack of an ideal natural surfactant material with adequate surfactant proteins, coupled with uncertainty about optimal timing, dosing and delivery method are some of the limitations of published surfactant replacement clinical trials. Recent advances in stable isotope labelling of surfactant phospholipids coupled with analytical methods using electrospray ionisation mass spectrometry enable highly specific molecular assessment of phospholipid subclasses and synthetic rates that can be utilised for phenotypic characterisation and individualisation of exogenous surfactant replacement therapy. Exploring the clinical benefit of such an approach should be a priority for future ARDS research.

Grand challenge: investigating the oxidant hypothesis in the realm of systems physiology and disease pathogenesis

Despite significant advancement in our understanding of the role of oxidative stress in disease pathogenesis, the majority of clinical trials examining antioxidant therapy and redox modifying interventions have failed to establish clinical benefit. The lack of clinical efficacy in human trials despite a wealth of literature demonstrating a clear pathogenic role of free radicals in disease states ranging from cardiovascular disease to cancer belies the need for research efforts into the role of oxidants in physiology. With the advent of new free radical detection techniques, advances in molecular biology and the development of in vivo free radical imaging modalities, the field is uniquely positioned to begin to unravel the molecular mechanisms of free radical injury and redox signaling within the realm systems physiology and disease pathogenesis. In this regard, the challenges we face lie in our ability to reconcile past discovery and current knowledge with future efforts to examine whether the oxidative modification hypothesis is relevant to human disease. The challenges begin with identifying viable therapeutic targets and approaches to restore redox balance and ameliorate free radical injury and the physiological disturbances resulting from oxidative stress. As a result of a large body of epidemiological data showing a protective role for dietary antioxidants, numerous clinical trials have been initiated to examine the benefit of supplementation with dietary antioxidants primarily focusing on vitamin E, vitamin C, or s-carotene (Jha et al., 1995). Unfortunately, in the majority of studies, antioxidants are looked on as a class of compounds sharing certain common properties that are functionally considered interchangeable. There may be some justification for such classification when dealing with simple in-vitro redox systems, however, there are striking differences with regards to there chemical properties. For example, s-carotene is an excellent scavenger of singlet oxygen but much less effective at terminating free radical chain reactions; the reverse is true of vitamin E (Packer et al., 1981). In the context of a complex biological system, such aggregate classification becomes hard to defend. For example, vitamin C is water-soluble, readily absorbed, and transported in the aqueous phase of the plasma; vitamin E is lipophilic, poorly absorbed in the GI tract, and transported with plasma proteins (Padayatty et al., 2004; Rigotti, 2007). The pharmacodynamics of the various antioxidants also differ greatly, and until we know where and how these agents function, we have no way to predict which antioxidant, at what dosage and administered by what route, will be most effective. An analysis of the hypothesis and the trial literature, points out major misconceptions about the hypothesis and unjustified outcome expectations of antioxidant trials. In response, future efforts in the field of oxidant physiology should include: (1) identification of novel and selective biochemical and biological markers of oxidative stress; (2) informed antioxidant selection based on comprehensive pharmacokinetic profiles and identification of physiological targets of action; and (3) establishment of selection criteria for patient recruitment. Through their effects on proteins, DNA and membranes, oxidizing and reducing agents play a critical role in regulating a myriad of cellular functions. Our goal is to publish research related to furthering the understanding of the integrative mechanisms of redox signaling in the control of complex physiological function. This aspect is critical to our ability to understand, manage and treat diseases associated with oxidant stress and impaired antioxidant defenses. Because of the integrative nature of the specialty section, the scope of articles that will be considered is broad, and includes work elucidating genetic, biophysical, genomic, proteomic, cellular, molecular, biochemical, physiological and pharmacological aspects of oxidants and redox active molecules, as well as the pathological events associated with oxidants stress. Free radical imaging studies and clinical studies targeted to mechanistic aspects of oxidative stress are also welcome. In conclusion, new technologies and animal models of disease will continue by ingenious innovations to make inroads in our understanding of the role oxidants play in physiology and medicine. The use of novel molecular, genetic and imaging approaches will undoubtedly provide fundamental advances in the realm of oxidant physiology. This is the good news! The bad news is that we need to wait to find out how.

The Selective 5-Hydroxytryptamine 1A Antagonist, AZD7371 [3(R)-(N,N-Dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (R,R)-tartrate Monohydrate] (Robalzotan Tartrate Monohydrate), Inhibits Visceral Pain-Related Visceromotor, but Not Autonomic Cardiovascular, Responses to Colorectal Distension in Rats

5-Hydroxytryptamine 1A (5-HT(1A)) receptors have been suggested as a target for the treatment of irritable bowel syndrome (IBS). A recent clinical trial investigating the efficacy of the selective 5-HT(1A) antagonist AZD7371 [3(R)-(N,N-dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (R,R)-tartrate monohydrate] showed no symptomatic improvement in IBS patients. We characterized the mechanisms mediating potential analgesic effects of AZD7371 in a model of colorectal distension (CRD)-induced visceral pain in rats to understand its mechanism of action and the lack of clinical efficacy. Visceromotor and cardiovascular responses (telemetry) were assessed in conscious rats during noxious CRD (80 mm Hg). Effects of AZD7371 (3-300 nmol/kg i.v.; 1-30 micromol/kg p.o.) and a reference 5-HT(1A) antagonist, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide maleate salt; 3-300 nmol/kg i.v.), were assessed. Effects of intracerebroventricular AZD7371 were also evaluated. Intravenous AZD7371 or WAY-100635 and oral AZD7371 dose-dependently inhibited visceromotor responses to CRD (ED(50), 203, 231, and 14 micromol/kg, respectively). In telemetrized rats, oral AZD7371 inhibited visceromotor responses to CRD without affecting the concomitant hypertensive and tachycardic responses. Intracerebroventricular AZD7371 did not affect visceromotor responses, whereas it inhibited micturition. None of the doses tested induced visible gross side effects. AZD7371, likely acting at a spinal site, inhibited the visceromotor but not the cardiovascular responses to visceral pain in the CRD model in rats. Although agents effective on multiple pain-related readouts in the CRD model (e.g., pregabalin or clonidine) alleviate IBS symptoms, AZD7371, which is effective on only one pain-related pseudoaffective readout, does not. Data from preclinical CRD models of visceral pain need to be interpreted cautiously as it relates to their clinical translational value.

Failure is an option: learning from unsuccessful proof-of-concept trials

Recent statistics indicate that the attrition rates during drug development remain high. Lack of clinical efficacy has meanwhile become the most frequent cause for discontinuation of a drug development program. Consequently, attrition rates are highest in clinical Phase II, which usually includes the first evidence for pharmacodynamic action of the compound or, proof of concept. Interestingly, attrition is approximately 60-70% across a variety of therapeutic areas, including the central nervous system (where predictivity of animal models is usually low) and cardiovascular medicine (where animal models are considered to be more predictive). Obviously, the translation of animal data into clinical benefit remains suboptimal.

Safety, immunogenicity, and clinical response of a survivin-based peptide vaccine in therapy-resistant advanced cancer: Results from a phase I/II trial

3046 Background: Therapeutic vaccination of cancer patients with detectable disease is followed only in few cases by objective tumor regressions despite. This lack of clinical efficacy has been attributed to various immune escape mechanisms including down-regulation or loss of expression of the targeted antigen; hence, antigens essential for the oncogenic phenotype should be more effective. To this end, survivin is essential for the survival of the cancer cell. Methods: The tolerability, immunogenicity, and clinical efficacy of 3 survivin peptides restricted to HLA A1, A2 and B35 were addressed in patients with advanced solid tumors. According to their HLA haplotype patients were vaccinated with 1 to 3 peptides. 3 consecutive vaccination protocols were tested: (i) 100 μg of peptide emulsified in Montanide ISA-51 as deep s.c. injections on d1, d8, d28, and then every 28 days, (ii) weekly injections until d56 followed by monthly injections, and (iii) the latter schedule preceded by a single i.v. bolus of 250 mg/m2 cyclophosphamide. Results: In total, 79 patients with metastatic melanoma (n=61), pancreatic (n=8), cervical (n=5), colorectal (n=2), adrenal gland (n=2), and merkel cell carcinoma (n=1) who failed to respond to systemic standard therapy were included. Frequently observed toxicities included transient grade 1/2 injection site reactions, grade 1 fever and painless swelling of the lymph nodes draining the vaccination site. No signs of autoimmunity or impaired wound healing were observed. Vaccine-specific immune responses were induced in 50% of the patients with a trend to a higher responder rate in the frequency-intensified schedules, which was not further increased by addition of prior cyclophosphamide. Clinical virtue, i.e. objective responses and control of disease, were essentially restricted to immunological responders. 3 complete responses and 3 partial responses were observed with duration of response ranging from 3 to 36+ months (OR=7.6%). Conclusions: Peptide vaccination against the inhibitor of apoptosis protein survivin is safe and elicits tumor specific CD8+ T cells. Encouraging clinical responses in these patients with therapy-refractory cancer warrants further development of this vaccine. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Merck Merck

Is B-Raf a Good Therapeutic Target for Melanoma and Other Malignancies?

The RAF family members, A-Raf, B-Raf, and C-Raf (or Raf-1), are intermediate molecules in the mitogen-activated protein (MAP) kinase [Ras/Raf/MAP kinase/extracellular signal-regulated kinase (Erk) kinase (MEK)/Erk] pathway, which relays extracellular signals from the cell membrane to the nucleus via a cascade of phosphorylation events ultimately promoting cancer development. This pathway is activated by mutation in approximately 7% of all human cancers. B-Raf is one of the proteins frequently mutated to an active form during tumor development. Therefore, B-Raf is an attractive cancer target but lack of clinical efficacy using agents targeting this protein has raised serious doubts about its therapeutic utility. Design of more effective B-Raf inhibitory agents, targeting other members of the signaling cascade for greater clinical efficacy or inhibiting B-Raf in combination with other targets, is being evaluated to resolve these perplexing issues. Here, we discuss recent progress, using preclinical models and clinical studies, to resolve the controversy of whether B-Raf would be a good therapeutic target for melanoma and other malignancies.

Lack of clinical efficacy of rituximab in the treatment of autoimmune neutropenia and pure red cell aplasia: implications for their pathophysiology

We describe 11 patients with severe refractory autoimmune cytopenias treated with the anti-CD20 monoclonal antibody rituximab. Six patients had autoimmune neutropenia (AIN), two had pure red cell aplasia (PRCA), one had AIN and autoimmune haemolytic anaemia, one had AIN and immune thrombocytopaenia purpura (ITP) and one had PRCA and ITP. Rituximab was administered at a dose of 375 mg/m(2) as an intravenous infusion weekly for 4 weeks. Six of eight patients with AIN and all three patients with PRCA did not respond. Two patients died: one with resistant AIN and autoimmune haemolytic anaemia died of pneumocytis pneumonia infection, and one with PRCA and ITP died of an acute exacerbation of bronchiectasis. Rituximab in AIN and PRCA appears to be less effective than Campath-1H when compared to historical data from our group. This supports the hypothesis that T cells may be important in the pathophysiology of AIN and PRCA.

Safety and Compliance of Intravenous and Oral Dosing Regimens

The Oncologist 2005;10:313–314 www.TheOncologist.com The recent article by Conte and Guarneri highlights numerous safety and compliance issues of intravenous and oral bisphosphonates in patients with metastatic bone disease [1]. I believe it is essential that readers of The Oncologist are made aware of a few of the inaccuracies within the article, particularly those renal safety statements that contradict the approved product labeling for ibandronate. First, the authors imply that the nephrotoxic potentials of intravenous bisphosphonates are similar. This is misleading. The product labeling for zoledronic acid contains a number of renal safety cautions not contained in the label of other bisphosphonates like ibandronate. In 2004, the US labeling for zoledronic acid was updated three times to provide additional safety guidance, and renal safety letters were sent to European physicians [2-4]. Various studies have reported renal safety issues with zoledronic acid [5-11], yet these are not discussed by Conte and Guaneri. For example, the Food and Drug Administration has received reports of renal deterioration progressing to renal failure and dialysis with the use of zoledronic acid [6]. Moreover, in a retrospective review, 23% of patients receiving zoledronic acid had substantial deterioration in renal function [8]. In contrast to zoledronic acid, available data suggest that ibandronate has a renal safety profile comparable to placebo [12-15]. Unlike zoledronic acid, monitoring of renal function is not required prior to each infusion of ibandronate. The approved product labeling for ibandronate in the European Union states that “according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with ibandronate” (i.e., monitoring with ibandronate is at the discretion of the physician) [12]. The statements by Conte and Guarneri about the use of ibandronate in patients with severe renal impairment (page 32) are somewhat unsubstantiated and imply a lack of clinical efficacy. According to the approved product labeling, both the oral and intravenous formulations of ibandronate can be used with a dose adjustment to compensate for lost renal excretion in patients with severe renal failure (creatinine clearance <30 ml/min), unlike zoledronic acid where it is contraindicated [12, 16]. Clearly, the conclusion of the abstract that “newer, more potent bisphosphonates ... can be administered via relatively short i.v. infusions without adversely affecting renal function” is unjustified for zoledronic acid. Due to time constraints, many physicians rely entirely on reading the abstract, hence patient safety could be compromised. It is important that physicians appreciate the differences between bisphosphonates to make informed treatment decisions.

A possible pharmacological explanation for quinacrine failure to treat prion diseases: pharmacokinetic investigations in a ovine model of scrapie

Quinacrine was reported to have a marked in vitro antiprion action in mouse neuroblastoma cells. On compassionate grounds, quinacrine was administered to Creutzfeldt-Jakob disease patients, despite the absence of preclinical in vivo studies to evaluate efficacy. Quinacrine failed to provide therapeutic benefit. The aim of the study was to investigate possible pharmacokinetic and/or pharmacodynamic explanations for the discrepancy between the proven action of quinacrine in vitro and its lack of clinical efficacy. We conducted in vitro experiments reproducing the culture conditions in which antiprion effects had been previously observed and recalculated the EC(50) by determining the actual extracellular (120 nM) and intracellular (6713 nM) quinacrine neuroblastoma concentrations with the reported quinacrine EC(50) (300 nM). A randomized clinical trial in scrapie-affected ewes confirmed the absence of therapeutic benefit of quinacrine. The in vivo quinacrine exposure was evaluated in a pharmacokinetic investigation in healthy ewes. Cerebrospinal fluid concentrations (<10.6 and 55 nM after administration of therapeutic and toxic quinacrine doses, respectively) were much lower than the quinacrine extracellular neuroblastoma concentrations corresponding to the reported EC(50). The total brain tissue concentrations (3556 nM) obtained after a repeated therapeutic dosage regimen were within the range of the intracellular neuroblastoma quinacrine concentrations. In conclusion, in order to avoid in vivo trials for which failure can be predicted, the measurement in vitro of the antiprion EC(50) in both intra- and extracellular biophases should be determined. It can then be established if these in vitro antiprion concentrations are achievable in vivo.

Pharmacological and biological evaluation of a series of substituted 1,4-naphthoquinone bioreductive drugs

The indolequinone compound EO9 has good pharmacodynamic properties in terms of bioreductive activation and selectivity for either NAD(P)H:quinone oxidoreductase-1 (NQO1)-rich aerobic or NQO1-deficient hypoxic cells. However, its pharmacokinetic properties are poor and this fact is believed to be a major reason for EO9's lack of clinical efficacy. The purpose of this study was to develop quinone-based bioreductive drugs that retained EO9's good properties, in terms of bioreductive activation, but have improved pharmacokinetic properties. Out of 11 naphthoquinone compounds evaluated, 2-aziridinyl-5-hydroxy-1,4-naphthoquinone (compound 2), 2,3-bis(aziridinyl)-5-hydroxy-1,4-naphthoquinone (compound 3), and 2-aziridinyl-6-hydroxymethyl-1,4-naphthoquinone (compound 11) were selected for further evaluation based on good substrate specificity for NQO1 and selectivity towards NQO1-rich cells in vitro. Compound 3 was of particular interest as it also demonstrated selectivity for NQO1-rich cells under hypoxic conditions. Compound 3 was not metabolised by murine whole blood in vitro (in contrast to compounds 2, 11 and EO9) and pharmacokinetic studies in non-tumour-bearing mice in vivo (at the maximum soluble dose of 60 mg kg −1 administered intraperitoneally) demonstrated significant improvements in plasma half-life (16.2 min) and AUC values (22.5 μM h) compared to EO9 ( T 1/2 = 1.8 min, AUC = 0.184 μM h). Compound 3 also demonstrated significant anti-tumour activity against H460 and HCT-116 human tumour xenografts in vivo, whereas EO9 was inactive against these tumours. In conclusion, compound 3 is a promising lead compound that may target both aerobic and hypoxic fractions of NQO1-rich tumours and further studies to elucidate its mechanism of action and improve solubility are warranted.

Duplicate publication.

Raja et al. take the defense for small-dose dopamine and do not accept the available evidence for advising against the use small-dose dopamine in the ICU. We agree with these authors that extrapolating data from animal studies or from human studies measuring surrogate markers of outcome to the clinical practice should be done with great caution. It is exactly this kind of misinterpretation that has lead to the multiple doubtful recommendations for the use of small-dose dopamine in the past. However, a well-designed, large, prospective, randomized, placebo-controlled clinical trial has showed that small-dose dopamine does not prevent or reverse acute renal failure, nor does it improve outcome (1). In addition, two meta-analyses were performed very carefully and came to the same conclusion (2,3). Besides the lack of clinical efficacy, small-dose dopamine has multiple side effects, as revealed form well-controlled clinical studies (4). We thus conclude that there is sound scientific evidence that no longer justifies the use of small-dose dopamine in the ICU. Yves A. Debaveye, MD Greet H. Van den Berghe, MD, PhD Department of Intensive Care Medicine, Catholic University of Leuven, Leuven, Belgium

NCCLS perspectives in changing susceptibility breakpoints for antimicrobial drugs

The spread of resistance to many antimicrobial agents in various microbial species has been highlighted by the World Health Organisation and many government agencies around the world. The reasons for this increase and spread are complex and are discussed. A number of surveillance studies has monitored the increase in resistance among isolates of Streptococcus pneumoniae to various important classes of antimicrobials. These results are discussed with particular reference to penicillins, macrolides and fluoroquinolones. Although there is evidence that in vitro resistance to macrolides and more recently to fluoroquinolones may be associated with a reduced clinical efficacy, there is no such clear association with resistance to β-lactams and lack of clinical efficacy in non-meningeal infections. Resistance or susceptibility to an antimicrobial agent is based on breakpoints and these are set in the US by the National Committee of Clinical and Laboratory Standards. In response to these recent clinical studies showing that non-meningeal pneumococcal infections with strains classified as resistant in vitro still responded well to treatment with various β-lactams, new breakpoints have been set. Results are presented showing that using these breakpoints, the levels of resistance to the third generation cephalosporins, ceftriaxone and cefotaxime against a range of non-meningeal pneumococcal isolates were lower than those obtained using the previous breakpoints. The excellent pharmacokinetic and pharmacodynamic properties of these agents are believed to contribute to their good activity in the clinic.

Mechanical devices for cardiopulmonary resuscitation: an update

Despite the promise and universal use of the Kouwenhoven technique for closed chest cardiac massage, this method has been shown repeatedly to suffer from lack of clinical efficacy. Although the Kouwenhoven technique can clearly save lives, the inherent inefficiency of this approach and the challenges related to teaching and retaining the skills needed to perform the technique correctly have limited its overall effectiveness. This has prompted the development of newer lifesaving CPR techniques and devices. Some of the advances, such as the vest approach, active compression-decompression, and the impedance threshold valve, offer a benefit when compared with the Kouwenhoven technique. It is clear, however, that challenges related to implementation of these newer approaches will determine their ultimate utility. It is not sufficient to have a better technique or device available. Challenges to implementation of the newer approaches include overcoming the inertia of a universal mindset on the already-familiar Kouwenhoven technique and creating a cost-effective justification for change. Each year, approximately 10 million people in the United States are trained in the Kouwenhoven technique. Americans spend nearly $500,000,000 annually on this form of CPR training and retraining. Given the less than 5% survival rate for the 300,000 patients who experience out-of-hospital cardiac arrest each year in the United States, the prudence of this societal investment when compared with other ways health care dollars are spent should be questioned. It is hoped that this mismatch between costs and benefits will be recognized and will lead to the adoption of more effective means to resuscitate patients.

Lack of clinical efficacy of pharmacologic treatment of the no-reflow phenomenon despite significant angiographic improvement Marco V. Wainstein, Frederic S. Resnic, Michael K. Y. Lee, Rodrigo V. Wainstein, Dominik Behrendt, Lucila Ohno-Machado, James M. Kirshenbaum, Campbell Rogers, Robert N. Piana, Jeffrey J. Popma. Brigham and Women's Hospital, Boston, MA, Vanderbilt University Medical Center, Nashville, TN

Lack of clinical efficacy of pharmacologic treatment of the no-reflow phenomenon despite significant angiographic improvement Marco V. Wainstein, Frederic S. Resnic, Michael K. Y. Lee, Rodrigo V. Wainstein, Dominik Behrendt, Lucila Ohno-Machado, James M. Kirshenbaum, Campbell Rogers, Robert N. Piana, Jeffrey J. Popma. Brigham and Women's Hospital, Boston, MA, Vanderbilt University Medical Center, Nashville, TN

THERAPEUTIC STUDIES

This article discusses the problems in basic design, conduct, and interpretation associated with phases I, II, and III of the cancer clinical trials and explains the various statistical solutions to these problems. The fundamental problem common to all three trials is achieving a correct and precise answer to the question posed to inform future testing and treatment while protecting trial patients from receiving treatment that has demonstrated excessive toxicity or lack of clinical efficacy. This shared problem gives rise to statistical designs with basic similarities across the three trial types.

An overview of age-specific pharmacokinetics and pharmacodynamics

The body's handling of drugs can be significantly altered with age. An overview of the way the body manages the movement of drugs through the body, pharmacokinetics, and their interaction with the body to cause their effects, pharmacodynamics, is provided. Clinically significant changes rather than those seen only in laboratory-controlled conditions are stressed. Some specific drug categories that present increased risk for older patients (psychoactive drugs, non-steroidal anti-inflammatory drugs, histamine-2 antagonists and warfarin) are reviewed in detail. In summary, there are numerous changes in drug pharmacokinetics and pharmacodynamics with aging. Some of these can be clinically significant, causing adverse effects or lack of clinical efficacy. Knowledge of the mechanisms, and specific drugs at-risk, will enable practitioners successfully to prescribe drugs even from the high-risk categories.

Pharmacologic options for the overactive bladder

Objectives. To review the current pharmacologic options for treatment of the overactive bladder and to describe potential therapies on the horizon. Methods. The literature on the clinical efficacy and safety of the currently available agents is described. Results. According to the guidelines issued by the Agency for Health Care Policy and Research (AHCPR), anticholinergic agents should be the first-line pharmacologic therapy for patients with detrusor instability. Oxybutynin is the anticholinergic of choice for this indication, whereas propantheline is the second-line therapy. Although calcium antagonists have been investigated, the one such drug introduced for the treatment of overactive bladder (terodiline) was withdrawn from the market because of a risk of cardiac arrhythmia. Studies of potassium channel openers have found either a lack of clinical efficacy or an unacceptable level of side effects. Alpha-adrenergic antagonists may be useful for decreasing bladder overactivity in patients who have autonomous bladders as the result of conditions such as spinal cord injury. Tricyclic antidepressants (particularly imipramine) may be effective in decreasing bladder contractility, although the AHCPR guidelines caution that these drugs should be reserved for use in carefully evaluated patients. Future developments in the treatment of detrusor overactivity are likely to occur in 3 categories: drugs that affect peripheral excitatory mechanisms, drugs that inhibit afferent mechanisms, and drugs that affect more central actions at either the ganglionic, spinal cord, or supraspinal level. Conclusions. Although pharmacologic management of the overactive bladder has progressed little in the past 10 years, the future may hold the promise of more effective therapies.

Postoperative analgesia using a low-dose, oral-transdermal clonidine combination: Lack of clinical efficacy

To determine if a lower than previously reported oral-transdermal clonidine regimen could reduce postoperative morphine requirements without producing systemic side effects. Double-blind, randomized, placebo-controlled study. University-affiliated hospital. 29 healthy, ASA physical status I and II females undergoing elective abdominal hysterectomy. Patients received preoperative oral clonidine 4 to 5 mu/kg and a 7 cm2 transdermal clonidine patch (0.2 mg/24 hours) or a placebo tablet and patch. Postoperative patient-controlled analgesia pumps provided morphine during the 48-hour study period. Morphine use, hemodynamic changes, and nonhemodynamic side effects were recorded. Additionally, visual analog pain scales (VAPS) and plasma concentrations of morphine and clonidine were measured. We found that low-dose clonidine had no potentiating effect on morphine analgesia. Postoperative morphine use, VAPS, and morphine plasma levels were similar between the control and clonidine-treated groups. Nevertheless, patients in the clonidine group experienced a significantly greater incidence of intraoperative and postoperative hypotension and bradycardia than did the control group. No differences were noted in the incidence of nonhemodynamic side effects. The low-dose oral-transdermal clonidine regimen evaluated failed to reduce postoperative morphine requirements, although patients who received clonidine were still at risk for developing hypotension.

Long‐term systemic therapy with dimethylfumarate and monoethylfumarate (Fumaderm®) in psoriasis

AbstractObjective The aim of this study was to assess the clinical efficacy of long‐term (&gt; 6 months) oral fumarate maintenance treatment regimen and to determine its adverse effect profile.Background We previously showed the efficacy of oral fumarate treatment in psoriasis. However, little is known about long‐term maintenance therapy with oral fumarates. Because of concern about renal toxicity and/or other potentially hazardous adverse effects, their role in the long‐term management of psoriasis is still controversial and limited.Methods Clinical data and laboratory parameters of 83 psoriasis patients who were treated with oral fumarates during an uninterrupted period of 6 or more months, were collected and subsequently analysed.Results In 31 of the 83 patients the oral fumarate therapy was discontinued preliminarily (&lt;6 months) because of intolerable adverse effects (9 patients), lack of clinical efficacy (16 patients), insurance refunding problems (4 patients) and lost to follow‐up (2 patients), A major improvement of the psoriasis was present in 41 of the 83 patients. Long‐term oral fumarate maintenance therapy was accompanied by subjective adverse effects, mainly flushing (28 patients) and gastrointestinal upset (15 patients) and by a relative lymphocytopenia (35 patients).Conclusion Oral fumarates are effective well tolerated drugs suitable for long‐term management of psoriasis. However, this systemic therapy still has to be considered experimental and should only be performed under strictly controlled conditions. The cause and the clinical relevance of the relative lymphocytopenia, which occurs in a high percentage of patients during long‐term oral fumarate maintenance treatment regimen are unknown and still have to be determined.

Long-term systemic therapy with dimethylfumarate and monoethylfumarate (fumaderm®) in psoriasis

Objective The aim of this study was to assess the clinical efficacy of long-term (>6 months) oral fumarate maintenance treatment regimen and to determine its adverse effect profile.Background We previously showed the efficacy of oral fumarate treatment in psoriasis. However, little is known about long-term maintenance therapy with oral fumarates. Because of concern about renal toxicity and/or other potentially hazardous adverse effects, their role in the long-term management of psoriasis is still controversial and limited.Methods Clinical data and laboratory parameters of 83 psoriasis patients who were treated with oral fumarates during an uninterrupted period of 6 or more months, were collected and subsequently analysed.Results In 31 of the 83 patients the oral fumarate therapy was discontinued preliminarily (< 6 months) because of intolerable adverse effects (9 patients), lack of clinical efficacy (16 patients), insurance refunding problems (4 patients) and lost to follow-up (2 patients). A major improvement of the psoriasis was present in 41 of the 83 patients. Long-term oral fumarate maintenance therapy was accompanied by subjective adverse effects, mainly flushing (28 patients) and gastrointestinal upset (15 patients) and by a relative lymphocytopenia (35 patients).Conclusion Oral fumarates are effective well tolerated drugs suitable for long-term management of psoriasis. However, this systemic therapy still has to be considered experimental and should only be performed under strictly controlled conditions. The cause and the clinical relevance of the relative lymphocytopenia, which occurs in a high percentage of patients during long-term oral fumarate maintenance treatment regimen are unknown and still have to be determined.