What's in a number?

Ten years ago, the first estimates of the existing number of drug targets were made. This month's issue features an article and poster that together summarize current drug targets and associated characteristics, providing a basis to better understand the potential for future therapeutic exploitation.     

Does calprotectin represent a regulatory factor in host defense or a drug target in inflammatory disease?

Calprotectin, a protein composed by two subunits of 8 and 14 kD respectively, is released by neutrophils in the biological fluids under inflammatory states. For instance, detection of calprotectin in faeces represents a diagnostic tool in the case of inflammatory bowel disease. Quite interestingly, calprotectin is increased in the stool of healthy newborns from day three up to day thirty and, physiologically, this increase may be interpreted as a defense mechanism against yeast and fungi. Therapeutic attempts at inhibiting the deleterious effect of calprotectin have been experimentally made by using lycoricinidol. This natural compound is able to hamper the calprotectin-induced apoptosis on the one hand. On the other hand, the same compound plays a prophylactic role in the course of experimental arthritis in rats.     

Acute hepatitis in a patient using a Chinese herbal tea ‐ a case report.

A case is presented of reversible acute hepatitis in a patient using a Chinese herbal tea. Upon identification of the tea mixture Aristolochia species, including A. debilis, which contains the highly toxic aristolochic acid, could be identified. We conclude that the acute hepatitis as described in this patient is most likely to be caused by (one of) the active ingredients of the Chinese herbal tea. Furthermore, this case illustrates that socalled natural products can cause unexpected severe adverse reactions.     

Clinical data services-start-up in a developing country

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Dextromethorphan metabolic phenotyping in a Chinese population

目的：建立中国人右美沙芬（ＤＭ）氧化代谢多态性的表型分型．方法：１２０名无血缘关系的中国人口服ＤＭ２０ｍｇ后，测定其尿中ＤＭ及其代谢物右啡烷（ＤＸ）浓度，并计算代谢比值（ＭＲ）．结果：氧化代谢缺陷率为０８％（１人）；快代谢者可明显区分为极快代谢者（７６人）和中速代谢者（４３人）．０－８ｈ内ＤＭ和ＤＸ的尿排百分率分别为０４％±ｓ０５％和２６％±ｓ１３％，但两者无性别差异．结论：右美沙芬代谢的表型分型为中国人异喹胍４位羟化（ＣＹＰ２Ｄ６）多态性提供了新的信息．     

Tarka® overdose in a young child

Tarka? is a combination antihypertensive medication composed of verapamil hydrochloride and trandolapril. A 3.5-year-old female was brought to our hospital due to a sleepy condition 7 hours after an accidental ingestion of six tablets of Tarka? containing 240 mg verapamil hydrochloride and 4 mg trandolapril in each tablet. Five hours after hospitalization, her condition deteriorated and arterial pressure progressively decreased despite the treatment. Finally, a temporary pacemaker was implanted, after which the vital findings began to return to normal values. The pacemaker was removed 13 hours after implantation as normal heart rhythm was observed. There are no reports of intoxication with fixed-dose combination products, especially Tarka?, in young children in the literature. Therefore, we believe that our report can provide an insight on the toxic dose of this drug in younger children. Clinicians should keep in mind that lethargy can be the first symptom of a possible clinical deterioration, even in normotensive and normorhythmic individuals.     

Donepezil in a chronic drug user—a potential treatment?

The objective of the current study was to explore the potential cognitive benefits of an anticholinesterase inhibitor, donepezil, in a former chronic drug user. A neuropsychological test battery composed of the vocabulary and matrix reasoning subtests of the Wechsler adult intelligence scale-III, measures of everyday executive functioning (behavioural assessment of the dysexecutive syndrome [BADS]), and verbal learning and memory tasks (California verbal learning test-II; Rivermead behavioural memory test) was completed at baseline, at 3 months after introducing donepezil, and at 3 months after donepezil was discontinued. After donepezil treatment, substantial improvements were found on tasks of nonverbal fluid reasoning (i.e. matrix reasoning) and other executive functioning tests (i.e. BADS). At entry into the study, poor academic performance and subjective problems with memory and concentration were reported, particularly after amphetamine use (i.e. MDMA and crystal methamphetamine); after donepezil treatment, dramatic increases in memory, concentration and academic achievement were observed. The finding of improvements in tests of executive functioning and in academic performance in this case study, together with the minimal adverse side effects of donepezil, warrants the investigation of controlled studies of cholinergic enhancement in chronic amphetamine and other drug users.     

Drug development in NZ: can a country be a cluster?

The aims of this research were to assess New Zealand's (NZ) growing drug development industry, and compare it with drug development and biotechnology clusters overseas. This article presents the results of questionnaires administered dutring interviews with 60 senior people representing the industry. It narrates their expertise, knowledge management, and innovative behaviors. NZ's industry comprises highly qualified, very experienced, and motivated people. Their organizations have particular expertise in drug discovery, which has arisen from long‐term government support for biomedical research. There is also significant expertise in early‐stage clinical development and contract clinical research. Knowledge sharing was rated as better within organizations than externally. The participants gave the highest ratings of their organizations' innovative performance to solving problems that had caused others difficulty, teamwork and having new ideas; they prefer informal methods of knowledge acquisition. These factors may reflect the NZ approach of applying ingenuity to solve problems and preference for casual and internal knowledge sharing. NZ has a hub of drug development activity; however, its size, limited resources, and remoteness from major markets may limit the development of a complete pharmaceutical industry. NZ could be promoted as a unique “country cluster” offering niche areas of expertise especially in drug discovery and clinical research. Drug Dev Res 73: 51–58, 2012. © 2011 Wiley Periodicals, Inc.     

Is there a world beyond bevacizumab in targeting angiogenesis in glioblastoma?

INTRODUCTION: Antiangiogenic approaches are currently the dominating experimental therapeutic strategy in glioblastoma. First enthusiasm was provoked by promising radiological response rates and an apparent clinical benefit with some of these agents. Major limitations include the modest number of durable responses, the lack of cytotoxic antitumor activity, of synergy when combined with chemotherapy and of an overall survival benefit. AREAS COVERED: We review the rationale as well as preclinical and clinical evidence for the future development of antiangiogenic agents in glioblastoma. The most prominent approach targets VEGF and includes agents such as the VEGF antibody bevacizumab, the VEGF receptor fusion protein aflibercept or the tyrosine kinase inhibitors cediranib and XL-184. Inhibition of angiogenic pathways by small molecules, for example, enzastaurin, or anti-integrin-based approaches, for example, cilengitide, represent alternative strategies. EXPERT OPINION: Enzastaurin and cediranib failed in randomized Phase III trials in recurrent glioblastoma, aflibercept in Phase II. By contrast, bevacizumab was conditionally approved in many countries. Recently completed Phase III trials for bevacizumab and cilengitide in the first-line setting will define the future role of these agents. This intense clinical trial activity reflects the hope that antiangiogenic agents will become part of the limited therapeutic options for glioblastoma.     

Thalidomide in cancer treatment: a potential role in the elderly?

There is increased interest in the treatment of cancer with thalidomide because of its antiangiogenic, immunomodulating and sedative effects. In animal models, the antitumour activity of thalidomide is dependent on the species, route of administration and coadministration of other drugs. For example, thalidomide has shown antitumour effects as a single agent in rabbits, but not in mice. In addition, the antitumour effects of the conventional cytotoxic drug cyclophosphamide and the tumour necrosis factor inducer 5,6-dimethylxanthenone-4-acetic acid (DMXAA) were found to be potentiated by thalidomide in mice bearing colon 38 adenocarcinoma tumours. Further studies have revealed that thalidomide upregulates intratumoral production of tumour necrosis factor-alpha 10-fold over that induced by DMXAA alone. Coadministration of thalidomide also significantly reduced the plasma clearance of DMXAA and cyclophosphamide. All these effects of thalidomide may contribute to the enhanced antitumour activity. Recent clinical trials of thalidomide have indicated that it has minimal anticancer activity for most patients with solid tumours when used as a single agent, although it was well tolerated. However, improved responses have been reported in patients with multiple myeloma. Palliative effects of thalidomide on cancer-related symptoms have also been observed, especially for geriatric patients with prostate cancer. Thalidomide also eliminates the dose-limiting gastrointestinal toxic effects of irinotecan. There is preliminary evidence indicating that the clearance of thalidomide may be reduced in the elderly. The exact role of thalidomide in the treatment of cancer and cancer cachexia in the elderly remains to be elucidated. However, it may have some value as part of a multimodality anticancer therapy, rather than as a single agent.     

Using a Serial Marker to Predict a Repeated Measures Outcome in a Cohort Design—Results of a Simulation Study

Abstract

Consider the cohort design and suppose that the outcome of primary interest is a continuous random variable observed repeatedly over time. Suppose that there is a second variable of clinical relevance which is also observed repeatedly. We are interested in assessing whether the “serial marker” is in some sense predictive of the primary outcome. We would also like to predict the trend for the primary outcome assuming that the clinical marker follows a profile of specific clinical interest. In series of earlier papers, we have addressed these issues by applying a bivariate repeated measures model. One regression model was prescribed to relate the primary outcome to important explanatory variables, while a second regression model was prescribed for the serial marker. In this paper, we perform a series of simulation studies to investigate the empirical properties of this approach. Bivariate repeated measures data were generated at random, and basic study parameters including the sample size, the number of time points, the degree of serial correlation within the clinical marker, and type of association between the serial marker and the primary outcome were varied. The ability of the methodology to capture the underlying relationship between the two set of repeated measures was assessed. The ability to predicting the primary outcome corresponding to a known marker profile of specific interest was examined.