Cyclooxygenase-2 activation mediates the proangiogenic effect of nitric oxide in colorectal cancer.

PURPOSE: Up-regulation of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) enzymes has been reported in colorectal cancer. We aimed at evaluating the possible interaction between the nitric oxide and COX-2 pathways, and its effect on promoting tumor angiogenesis. EXPERIMENTAL DESIGN: Expression of iNOS, COX-2, vascular endothelial growth factor (VEGF), and CD31 was analyzed in tumor samples and corresponding normal mucosa obtained from 46 surgical specimens. We also evaluated iNOS activity, prostaglandin E(2) (PGE(2)), cyclic GMP and cyclic AMP production in the same specimens. Nitrite/nitrate levels, and PGE(2) and VEGF production were assessed in HCT116 and HT29 colon cancer cell lines after induction and selective inhibition of the two enzyme pathways. RESULTS: A significant correlation was found between iNOS and COX-2 immunohistochemical expression. PGE(2) production significantly correlated with iNOS activity and cGMP levels. A significant correlation was also found among PGE(2) production, microvessel density, and VEGF expression. Coinduction of both iNOS and COX-2 activities occurred after lipopolysaccharide (LPS) and epidermal growth factor (EGF) treatment in HCT116 and HT29 cells. Inhibition of iNOS by 1400W significantly reduced both LPS- and EGF-induced PGE(2) production. Treatment with LPS, EGF, and arachidonic acid significantly increased VEGF production in the iNOS-negative/COX-2-positive HT29 cells. This effect was completely reversed by treatment with the selective COX-2 inhibitor celecoxib. CONCLUSIONS: Our data showed a prominent role of nitric oxide in stimulating COX-2 activity in colorectal cancer. This interaction is likely to produce a cooperative effect in promoting angiogenesis through PGE(2)-mediated increase in VEGF production.     

Adverse drug reactions. A critical review.

The data on adverse drug reactions (ADRs) are incomplete, unrepresentative, uncontrolled, and lacking in operational criteria for identifying ADRs. No quantitative conclusions can be drawn from the reported data in regard to morbidity, mortality, or the underlying causes of ADRs, and attempts to extrapolate the available data to the general population would be invalid and perhaps misleading. To evaluate the impact as well as the causes of ADRs, representative populations, including general hospital and ambulatory patients of all medical specialties, must be studied, and operationally defined criteria must be used to establish the presence of an ADR in a prospective study that incorporates appropriate control populations. Similar studies on the benefits of drug use are needed to provide perspective on the risk-benefit aspects of drug therapy. Until such studies are performed, estimates of the nature and scope of the ADR problem can be only guesses.     

The role of benzodiazepines in nonpsychiatric medical practice.

The benzodiazepines are widely prescribed by many physicians for patients with depression, anxiety reaction, circulatory disorders, digestive disorders, tension headache, and pain in chest and back. According to various studies there is reason to believe that benzodiazepines not only possess the anxiolytic effects universally attributed to them but may also ameliorate somatic complaints affecting such systems as the cardiovascular and the gastrointestinal. twhether the bensodiazepines affect organ systems known to be linked in important pathophysiological ways to the nervous system deserves further study.     

From DNA to NDA--the impact of recombinant DNA technology on new drug development

Man's long-standing efforts to alter living things through genetic manipulation have become reality. Recent advances in recombinant DNA technology have the potential to alter the drug-development process profoundly. The pharmaceutical industry has had to adjust its research efforts and develop new state-of-the-art laboratories. In addition to the standard biological and in vivo assays, many new tests are required, e.g., amino acid sequencing, high-pressure liquid chromatography, and radioimmunoassays. Academic researchers have played a vital role in developing the new biotechnology, supplying most of the basic scientific knowledge and the initial supply of the scientific work force. The recent shifting of support for scientific training from the government to the pharmaceutical industry has resulted in unprecedented academe-industry relationships. Universities now stand to profit significantly from patent rights resulting from biotechnology research efforts. While the advances in biotechnology have had considerable impact on the pharmaceutical industry and academia, they have thus far had only a minor impact on the regulatory process. To date, the preferred regulatory path appears to be modification of existing procedures through the issuance of guidelines, which can be updated as knowledge increases.     

Graphical analysis of multivariate pain data in analgesic trials

In order to compare analgesic treatments effectively one must measure pain over time. In a single-dose clinical analgesic trial one typically obtains repeated pain measurements from each patient during a relatively short period (4-6 hours). Such measurements constitute multivariate data, which are usually reduced by simple addition to a single derived pain measure for analysis of between-treatment differences. In this article we consider graphical procedures for the display of multivariate, clinical analgesic data. The first of these are the traditional time-effect curves, with added "standard error bars." We also examine a multivariate display, the biplot, which is based on principal component analysis. This technique provides a representation of the raw pain scores at each time of measurement by a vector originating from the origin of a two-dimensional graph. The multivariate pain scores of individual patients are summarized by points on the graph. Differences in pain scores over time (or between treatment groups) may be examined by relating points (or ellipses representing treatment groups) to different vectors. Using actual data from a postsurgical analgesic trial, we compare the two approaches and show that the multivariate approach is a useful addition to the standard technique for display of such data.     

Long-term weight control study. I (weeks 0 to 34). The enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo.

To investigate the value of anorexiant medications as an adjunct to other forms of weight control therapy, we studied 121 people in a 34-week, double-blind clinical trial of 60 mg extended-release fenfluramine plus 15 mg phentermine resin versus placebo added to behavior modification, caloric restriction, and exercise. Participants weighed 130% to 180% (154% +/- 1.2%, mean +/- SEM) of ideal body weight (1983 Metropolitan Life tables) and were in good health. By week 34, participants receiving active medication lost an average of 14.2 +/- 0.9 kg, or 15.9% +/- 0.9% of initial weight (n = 58), versus a loss of 4.6 +/- 0.8 kg or 4.9% +/- 0.9% of initial weight by subjects taking placebo (n = 54; p less than 0.001). On visual analog scales, participants rated fenfluramine plus phentermine as more helpful than placebo (50.3 +/- 0.5 versus 20.3 +/- 0.3) and not bothersome (fenfluramine plus phentermine, 17.4 +/- 0.3 versus 13.5 +/- 0.2). Blood pressure decreased and pulse remained unchanged in both groups. Dry mouth was the most common adverse effect in subjects receiving fenfluramine plus phentermine; all adverse effects decreased after 4 weeks. Only nine participants left the study in the first 34 weeks. Two subjects from each group left the study as a result of adverse effects. Overall, fenfluramine plus phentermine used in conjunction with behavior modification, caloric restriction, and exercise aided weight loss and continued to be efficacious for 34 weeks.     

A Training Program in Clinical Pharmacology

Recognizing the need for trained clinical investigators experienced in evaluating drugs, The Johns Hopkins University School of Medicine has instituted a fellowship program for training physicians in clinical pharmacology.

The program is flexible but encompasses certain basic requirements for qualification of applicants.

The course and training are discussed and the prerequisites and objectives described.     

Isolated neurofibroma of the stomach. Case report and review of the literature]

An uncommon case of gastric neurofibroma is described: it was an incidental finding during assessment for abdominal pain, possibly due to pancreatitis, in a 58 year old man, with no sign of von Recklinghausen's disease. The generic diagnosis of gastric wall neoplasia was made by CT scanning; the neoplasm was resected with wedge resection of gastric wall. Histological and ultrastructural examination revealed a neurofibroma. Gastrointestinal stromal tumors are rare occurrence and usually are of smooth muscle derivation: a small percentage arises from nerve sheet, but such a distinction is never sharp. Neurogenic gastric tumors are usually benign and only 10% of von Recklinghausen associated neurofibromas can undergo malignant transformation. Wide excision of the tumor appears therefore the treatment of choice.