Reviews on Recent Clinical Trials - Volume 2, Issue 1, 2007

Given the morbidity and treatment challenges posed by many disease states, prevention of these conditions would clearly be a preferable alternative. Over the past year, we have observed examples of progress in this direction, especially in the field of infectious diseases. The two most recent prevention strategies have been introduced this year. In October 2005, Merck announced that an investigational vaccine (quadrivalent human papillomavirus types 6, 11, 16, 18, recombinant vaccine) prevented 100 precent of high-grade cervical pre-cancers and non-invasive cervical cancers associated with human papillomavirus (HPV) types 16 and 18 in a recent phase III study (P<0.001) [1]. The analysis compared the vaccine to placebo in women who were not infected with HPV 16 and 18 at enrollment and who remained free of infection through the completion of the vaccination regimen. Women were followed for an average of two years after enrollment. This phase III study was a prospective, randomized, double-blind, placebo-controlled study with two vaccination groups. Women aged 16 to 26 years were randomized to receive a three-dose regimen of either vaccine or placebo at Day 1, Month 2, and Month 6. A total of 12,167 women were enrolled from 90 study centers worldwide. The most common vaccine-related adverse event reported was local discomfort at the injection site [1]. Of particular interest to dermatologists, this HPV vaccine demonstrated 100 percent efficacy in preventing genital warts, vaginal dysplasia, and vulvar dysplasia in another study (P<0.001) [2]. In this trial, 2261 sexually active women aged 16 to 23 received 1 inoculation with vaccine and then received additional vaccinations at 1 and 6 months. A similar group of 2279 agematched women received placebo vaccinations on the same schedule. The investigators determined that, of the women who were vaccinated according to the protocol, none developed genital warts, or high-grade vulvar or vaginal dysplasia. Forty cases (1.8%) of genital warts or precancerous lesions occurred in the placebo group [2]. This vaccine was approved in the United States in June 2006. Herpes zoster is another disease for which a new vaccine has been developed. The incidence and severity of this condition and and the associated postherpetic neuralgia increases with age, and we have an increasingly aging population. Oxman et al. [3] conducted a large study in order to determine if vaccination against varicella zoster virus (VZV) would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. They enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine (“zoster vaccine”). The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001) [3]. Reactions at the injection site were more frequent among vaccine recipients but were generally mild. The zoster vaccine was approved in May 2006, for prevention of herpes zoster in individuals 60 years of age and older. The application of vaccines represents a new and exciting paradigm in the treatment of dermatologic disease. The HPV and zoster vaccines will offer us assistance in treating two very challenging conditions, and offer our patients with these conditions the potential for improved quality of life. Disclosure: Dr. Weinberg is a member of the Speakers' Bureau for Merck. References [1] http://www.brightsurf.com/news/headlines/view.article.php?ArticleID=21282. Accessed November 19, 2006. [2] http://www.docguide.com/news/content.nsf/news/8525697700573E18852570DC0054023E. Accessed November 19, 2006. [3] Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005; 352: 2271-2284.

Mining of the human genome has revealed approximately 7000 novel proteins, which could serve as potential targets for the development of novel therapeutics. Of these, approximately 2000 are predicted to be G-protein coupled receptors. Within this group of proteins, a family of 18 mammalian receptors has recently been identified that appear to exhibit selectivity toward the so-called trace amines. The trace amines are a family of endogenous compounds with strong structural similarity to classical monoamine neurotransmitters, consisting primarily of 2-phenylethylamine, m- and ptyramine, tryptamine, m- and p-octopamine and the synephrines. The endogenous levels of these compounds are at least two orders of magnitude below those of neurotransmitters such as dopamine, noradrenaline and 5-HT. The effects of these low physiological concentrations have been difficult to demonstrate but it has been suggested that they may serve to maintain the neuronal activity of monoamine neurotransmitters within defined physiological limits. Such an effect of trace amines would make them ideal candidates for the development of novel therapeutics for a wide range of human disorders. Although the demonstration of a trace amine family of receptors has seen a resurgence of interest in these endogenous compounds, with recent articles reviewing trace amine pharmacological and physiological responses, the potential clinical utility of the trace amine receptors has not been specifically addressed. Historically, trace amines have been implicated in a diverse array of human pathologies ranging from schizophrenia to affective disorders to migraine. Recent studies have strengthened some of this historical data by linking trace amine receptor polymorphisms and mutations to distinct clinical conditions. The aim of the current article is to review the previous studies linking trace amines to human pathology in the context of the recently discovered trace amine receptors and evidence of the existence of trace amine receptor polymorphisms and mutations associated with such disorders. In addition, recent evidence linking trace amines to the development of drug dependence will be discussed.

More than half of patients with malignancy present with a pleural effusion at some time in their course. Recurrent malignant pleural effusions (MPE) impair functions and worsen the quality of life. Once a patient develops MPE, only mechanical drainage relieves pulmonary compression and dyspnea. Optimal treatment is however, still controversial. During January 2001 to January 2006, our group treated 48 patients with outpatient insertion of chronic indwelling pleural catheter (IPC), Pleurx (Pleurx™, Surgimedics, Denver Biomaterials, Denver, CO, USA). Primary malignancy of 48 patients included: 27 lung cancers, 11 mesotheliomas, 5 breast cancers, 3 colon cancers, 2 pancreas cancers and 1 ovarian cancer. Eligibility for IPC required prior thoracentesis with histological confirmation of malignancy and chest roentgenogram evidence of effusion. All patients treated were made aware of their prior malignancy and positive cytology for MPE. Major complications, as systemic or pleural infections, were not registered. Permanence mean time of IPC was estimated as 88 days. Median time of draining interval was 7.0 days with maximum amount of effusion drained off being 1000 ml. Pleurodesis occurred in 23 of 48 (47.92%) patients with a mean time of pleurodesis being 43 days. IPC allows ambulatory treatment with a safe and effective drainage of MPE and is an alternative treatment to procedures in use.

Cancers of the colon and rectum are a leading cause of cancer-related death in the United States and worldwide. The 5-year survival rates, in general, have improved over time for patients with colon cancer due to evolving preventative strategies, improved screening techniques and the recent development of more effective therapeutic agents. Unfortunately, the treatment for patients with locally advanced rectal cancer remains less studied. This review will highlight recently reported trials evaluating pre-operative versus post-operative treatment strategies. A discussion of ongoing trials incorporating conventional chemotherapy and radiation will be included as well as trials planned or ongoing that incorporate radiation and the targeted agents. Further work is required regarding the rational integration of these targeted agents and the optimal selection of patients that will most likely benefit.

More than half of acute myeloid leukemia (AML) diagnoses are currently made in patients older than 60 years. Furthermore, even if the age-specific incidence remains stable in the coming years, the incidence of AML in elderly people is expected to consistently increase, given the progressive ageing of the general population. Consequently, the treatment of the disease in aged individuals represents a daily challenge in clinical hematology. Several studies have shown that, in current practice, a high fraction of patients older than 60 years is negatively selected for inclusion in clinical trials that are based on intensive chemotherapy. Apart from performance status and comorbidity at diagnosis, other non-clinical factors can significantly affect therapeutic choice including the distance from hematologic institution, presence of a carer, physician's and patient's attitude, and the scientific interest of the physician in a given therapeutic programme. In daily practice, a combination of these factors results in relevant selection of patients for clinical trials. Clearly, preselection of patients with AML leads to misleading overly optimistic results in some studies. Treatment of AML in the elderly is difficult and well-controlled trials in this group of patients are uncommon. Frequently, higly selected patients are recruited to relatively small phase II unrandomised trials with complete remission (CR) rates ranging from 25 to 70 %. These figures may turn unrealistic in the current practice. The present article reviews results of most relevant studies addressing therapeutic results in elderly patients with AML. Questions to be addressed will include potential selection biases, results with conventional chemotherapy, the therapeutic potential of autologous and allogeneic stem cell transplantation and a critical review of results achieved with newly developed drugs.

The extraordinary success of imatinib in gastrointestinal stromal tumor (GIST) represents a model for molecularly targeted therapy of solid tumors. Research is currently going to identify the molecular basis of mechanisms of action and drug resistance. For the optimal management of the patients treated, a multidisciplinary approach, including medical oncologists, surgeons, pathologists, and radiologists is needed. In this article, we reviewed recent advances in the clinical management of GIST patients treated with imatinib, and in the knowledge of the molecular mechanisms that are basic to imatinib effects.

Transcranial Doppler sonography (TCD) is used to assess cerebral blood flow velocity in basal cerebral arteries and is a common tool for the diagnosis and follow-up of cerebrovascular disease. With more than 200 clinical studies using TCD published annually, indications for its use are expanding. The current article critically reviews standard and recent clinical applications for TCD including delayed vasospasm after subarachnoid hemorrhage, sickle cell disease, atherosclerosis of cranial vessels, ischemic stroke, brain trauma, brain death, carotid artery disease, cerebral venous thrombosis, intraoperative TCD monitoring, arteriovenous malformations, cardiac shunts and preeclampsia.

Nitric oxide (NO) is produced by the endothelial NOS (eNOS) in the intima and by the neuronal NOS (nNOS) in the adventitia of cerebral vessels. By activating soluble guanylyl cyclase, NO increases the production of 3'-5'cGMP, which relaxes smooth muscle cells and dilates the arteries in response to shear stress, metabolic demands and changes of pCO2 (chemoregulation). 3'-5'cGMP is then metabolized by phosphodiesterases (PDEs). Aneurysmal subarachnoid hemorrhage (SAH) interrupts this regulation of cerebral blood flow (CBF). Oxyhemoglobin, gradually released from the subarachnoid clot enveloping the conductive arteries, scavenges NO and destroys nNOS-containing neurons. This deprives the arteries of NO, leading to vasoconstriction which initiates delayed vasospasm. This arterial narrowing increases shear stress and stimulates eNOS, which under normal conditions would lead to increased production of NO and dilation of arteries. However, this does not occur because of transient eNOS dysfunction evoked by increased levels of an endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA). Increased ADMA levels result from decreased elimination due to inhibition of the ADMA-hydrolyzing enzyme (DDAH 2) in arteries in spasm by hemoglobin metabolites, bilirubin-oxidized fragments (BOXes). This eNOS dysfunction sustains vasospasm until ADMA levels decrease and NO release from endothelial cells increases. This NO-based pathophysiological mechanism of vasospasm suggests that exogenous delivery of NO, modification of PDE activity, inhibition of the L-arginine-methylating enzyme (I PRMT 3) or stimulation of DDAH 2 may provide new therapies to prevent and treat vasospasm. This paper summarizes experimental and early clinical data that are consistent with the involvement of NO in delayed cerebral vasospasm after SAH and which suggests new therapeutic possibilities.

The mortality and morbidity of tumors of the upper GI tract are formidable with incidence and mortality nearly the same. Therefore, better therapies are necessary, and these are generally molecularly targeted therapies. This chapter focuses on the treatment of pancreatic cancer with targeted therapy. Important cellular pathways are reviewed, including signal transduction, proteasome inhibition, cell cycle, anti-angiogenesis pathways, immunologic therapies, viral therapy, epigenetic therapies and microarray analysis. Signal transduction pathways include epidermal growth factor receptors, such as cetuximab and Tarceva, as well as other less well-defined pathways. Proteasome inhibition includes inhibition of the 26S proteasome with PS-341. Cell cycle therapies include inhibitors of all the proteins involved in pushing the cell through the cell cycle. Viral therapies mainly cover the adenoviruses, like ONYX-015, and Reolysin, a type 3 serotype Dearing strain with little pathogenicity. Immunological therapies include cytokines, vaccines and cell-based therapies. Epigenetic therapies are mainly centered around histone deacetylases. Microarray analysis analyzes expression of thousands of genes to create a tumor profile, mainly for prognosis or prediction. Various promising treatment strategies are reviewed in terms of treatment with molecularly-guided therapies. Complications of therapy, particularly rash and thrombosis are reviewed.

The obesity epidemic in the developed and developing world is being followed by an epidemic of type 2 diabetes. In type 2 diabetes, subjects cannot manage glucose properly because they do not produce enough insulin, and the peripheral tissues have become resistant to insulin. Glucagon-like peptide 1 (GLP-1) is an intestinal peptide hormone that is secreted in response to food to regulate the postprandial blood glucose concentration. One of the actions of GLP-1 is to stimulate insulin secretion. In subjects with type 2 diabetes, intravenous or subcutaneous GLP-1 stimulated insulin production and decreased blood glucose levels. However, as GLP-1 is rapidly metabolised, it is not suitable for use in most subjects with type 2 diabetes. Exendin-4 is a 39-amino acid peptide that acts as an agonist at the GLP-1 receptor. After subcutaneous administration, synthetic exendin-4 (exenatide) decreased postprandial concentrations of glucose and insulin, and fasting glucose levels in subjects with type 2 diabetes, and the effects lasted several hours. Subsequently, exenatide was been trialled in subjects taking metformin only, a sulfonylurea only, or metformin and a sulfonylurea, and shown to improve glycemic control with few adverse events, initially over 30 weeks, and then extended to 82 weeks. Exenatide may also be as effective as insulin glargine in subjects with type 2 diabetes not adequately controlled with the oral agents. In conclusion, exenatide represents a new and beneficial addition to the medicines used to treat type 2 diabetes.