Clinical pharmacological trial of guanazole.
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Abstract:
Summary Guanazole was given to 27 patients with advanced neoplastic diseases, mostly acute leukemia, by continuous i.v. infusion in 5-day courses. Toxicity was manifest mainly by myelosuppression, but drug fever, mucositis, rash, and alkalosis were also observed. Complete remission was achieved in two out of 14 patients with previously treated acute myelocytic leukemia, and an M1 marrow occurred in one out of four patients with advanced acute lymphocytic leukemia. Most of the effects of guanazole appear to be dose related, with a narrow therapeutic index. This is the first evidence of therapeutic activity of guanazole in man.Keywords:
Mucositis
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Despite significant need and historical trials, there are no effective drugs in use for the prevention or treatment of acute kidney injury (AKI). There are several promising agents in early clinical development for AKI and two trials have recently been terminated. There are also exciting new findings in pre-clinical AKI research. There is a need to take stock of current progress in the field to guide future drug development for AKI. Areas covered: The main clinical trial registries, PubMed and pharmaceutical company website searches were used to extract the most recent clinical trials for sterile, transplant and sepsis-associated AKI. We summarise the development of the agents recently in clinical trial, update on their trial progress, consider reasons for failed efficacy of two agents, and discuss new paradigms in pre-clinical targets for AKI. Agents covered include- QPI-1002, THR-184, BB-3, heme arginate, human recombinant alkaline phosphatase (recAP), ciclosporin A, AB103, levosimendan, AC607 and ABT-719. Expert opinion: Due to the heterogenous nature of AKI, agents with the widest pleiotropic effects on multiple pathophysiological pathways are likely to be most effective. Linking preclinical models to clinical indication and improving AKI definition and diagnosis are key areas for improvement in future clinical trials.
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Over the past decade, the biotechnology/pharmaceutical industry has been diligently working on the development of immunomodulatory agents for the treatment of shock and sepsis, and the literature is rife with descriptions of novel and innovative molecules that promise to become the panacea for these conditions. Unfortunately, despite promising preclinical evidence, dozens of these new agents have failed to demonstrate clinical efficacy in controlled, randomized clinical trials, abandoning the bedside physician to the traditional armamentarium of drugs and therapeutics for the treatment of patients with these complex, progressive, and life-threatening conditions. The reasons for this quandary are controversial, complex, and multifactoral. This review focuses on the concept that the preclinical trials of many of these agents were conducted using models of sepsis and shock that do not adequately reflect the clinical realities of these conditions. As a result, it is not surprising that clinical trials of agents based on clinically flawed models failed to demonstrate clinical efficacy. The lack of clinical insight during preclinical development of these agents has contributed to the current impasse of the development of safe, efficacious, and potentially lifesaving agents for the treatment of shock and sepsis. Thus, the goal of this review article is to review the advantages and disadvantages of commonly used sepsis and shock models in light of lessons learned from these clinical trials.
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Purpose of review Invasive fungal infections, such as invasive candidiasis and aspergillosis, are increasingly important in the critical care setting. This review will focus on clinical trials of antifungals in this setting and the methodological issues surrounding them. Recent findings Critically ill patients have traditionally only comprised a fraction of the patients enrolled in clinical trials exploring antifungal use, but recently a few clinical trials with specific therapeutic approaches have focused on this subpopulation. Increased mortality and problems with diagnosis have fostered the development of new management strategies, such as prophylaxis, pre-emptive treatment, and empirical antifungal therapy. Summary Although there are limited data supporting preventive and early therapeutic strategies, their use is recommended in highly selected patients and settings. Although critically ill patients are under-represented in clinical trials of antifungals conducted for the purpose of licensing, most experts agree that it is reasonable to extrapolate from these data until specific trials are conducted.
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Sepsis syndrome and septic shock remain as significant causes of morbidity and mortality. To date, clinical trials of immunotherapeutic agents have failed to establish conclusively a role for these agents despite considerable animal data to suggest a positive benefit. This article discusses the hypotheses upon which these therapies are based, the critical issues associated with clinical trials and the molecules which have been clinically tested. Recommendations for future clinical trials in sepsis are made.
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Acute kidney injury (AKI) is associated with a heavy burden of morbidity and mortality, despite advances in intensive care and the management of high-risk patients. Numerous clinical trials have failed to ameliorate the outcomes of AKI. The proposal and validation of standardized definitions and staging criteria for AKI has been an important step in improving the conduct of clinical trials in this population. Similarly, a multidisciplinary dialogue is making progress towards standardization of the clinical trial endpoints to prove efficacy and effectiveness in AKI research. Taken together with the increasing availability of timely, sensitive, and specific novel biomarkers of kidney damage, we are poised to use these tools to conduct successful clinical trials of agents for the prevention and treatment of this devastating clinical syndrome.
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Acute kidney injury is associated with significant morbidity and mortality in hospitalized patients. Clinical trials for acute kidney injury have been hampered not only by a paucity of appropriate potential therapeutic agents, but also by several clinical trial design challenges. First, for novel therapies to have the best chance at efficacy, early patient identification is critical. Second, for certain novel therapies with a mechanism of action directed at the underlying disease state (e.g., sepsis) or a specific pathogenic process, careful disease phenotyping may be required. Third, even among patients with AKI, risk stratification may be required to select a higher-risk subset for clinical trials. Finally, clinical endpoints for clinical trials must be considered carefully, as patients may die for reasons unrelated to AKI, including withdrawal of support. However, these challenges are not unique to AKI; some possible solutions including alternative endpoints used in other clinical trial settings are reviewed here.
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Abstract Outcomes after lung transplantation remain disappointing because there is a high incidence of chronic lung allograft dysfunction (CLAD), which typically follows a progressive clinical course and often results in allograft failure and death. Chronic rejection is considered the predominant cause of CLAD. Thus, optimal immunosuppression has been viewed as having the potential to prevent CLAD and improve survival after lung transplantation. Numerous clinical trials have been conducted investigating the efficacy and safety of various immunosuppressive agents. Many studies have been small and single-center clinical trials but some have been international and multicenter trials enrolling more than 300 patients. This review focuses on clinical trials of immunosuppression conducted in lung transplantation and points out strengths and limitations of the various studies. Ultimately, the findings of these clinical trials explain the current state of practice in lung transplantation and identify gaps in knowledge that require additional study. Finally, there is an ongoing need for carefully designed and conducted clinical trials to improve clinical practice and outcomes after lung transplantation.
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The validity of the results of a clinical trial is highly dependent upon the design of the trial. The definition of disease, the selection criteria for enrollment in the trial, the selection of the study and control drugs, and the end points all affect whether the information obtained from the trial ultimately is useful in making decisions in clinical practice. These factors all apply to the design of clinical trials of the prophylaxis of infectious diseases. In addition, prophylaxis trials have several important differences from the design of trials of the treatment of those same diseases. The risk-benefit analysis for trials of prophylaxis is different, in that asymptomatic patients are exposed to the drug and more patients will be exposed than will develop the disease under study. Standardization of the design of such clinical trials will allow more efficient development of new drugs and will allow clinicians to compare more accurately the safety and efficacy of prophylactic agents.
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