Novelties in the field of anti-infectives in 1998.
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In 1998, about 30 new medicinal chemical entities in the field of antibacterials and antifungals were presented during the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, held in San Diego. Among these compounds, only a few of them seem to be candidates for preclinical and clinical development: GAR 936, RWJ 54,418, ME 1209, L-084, FK 483, and DC 756. Other compounds seem to be in the preselection stage or potential lead compounds. (+info)
Clinical strategy for the development of angiogenesis inhibitors.
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Angiogenesis inhibitors differ from conventional cytotoxic chemotherapy agents by targeting normal cells rather than tumor cells, which may contain multiple mutations. Because of this, the traditional strategy used in clinical development of cytotoxic agents may not be appropriate for these novel agents. Many clinical studies are now evaluating these agents with a new approach, referred to as the cytostatic paradigm. The cornerstone of the cytostatic paradigm is the use of time to progression (TTP) of disease as the decision-making criterion for "go/no go" in the early phases of clinical development. However, the use of TTP as the main criterion for clinical trials is complicated for a variety of reasons, including: A) the lack of standardized criteria accepted by regulatory authorities; B) the heterogeneity of the historical database, and C) the larger number of patients needed for the "go/no go" decision-making process. In addition, clinical trials of cytotoxic agents have traditionally used objective response (despite the controversy regarding objective response as a surrogate for clinical activity) as the main criterion for determining whether the results of phase II studies justify the pivotal phase III studies. Another aspect of the clinical development strategy is combining angiogenesis inhibitors with cytotoxic chemotherapy. The rationale for combination of angiogenesis inhibitors with cytotoxic agents is based on: A) different targets for these agents; B) lack of cross-resistance patterns; C) lack of myelosuppression with angiogenesis inhibitors allows administration of full doses of all agents, and D) the assumption that combining these agents will result in additive antitumor activity. Combination therapy with angiogenesis inhibitors may be attractive to both clinicians and their patients because it allows cytostatic agents to be used upfront in treatment while contributing to drug registration strategy (cytostatic/cytotoxic combination therapy versus cytotoxic therapy). The clinical development of the angiogenesis inhibitor SU5416, a small molecule inhibitor of vascular endothelial growth factor, is currently ongoing. In phase I trials, SU5416 demonstrated activity in both colorectal and non-small-cell lung cancer patients. Based on these encouraging results, phase III studies to evaluate combination of SU5416 with established cytotoxic therapy are planned. These studies will include an interim analysis, the equivalent of a phase II evaluation of clinical activity. If successful, this strategic approach will save significant time in the clinical development process. (+info)
Bioassays of shortened duration for drugs: statistical implications.
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Declining survival rates in rodent carcinogenesis bioassays have raised a concern that continuing the practice of terminating such studies at 24 months could result in too few live animals at termination for adequate pathological evaluation. One option for ensuring sufficient numbers of animals at the terminal sacrifice is to shorten the duration of the bioassay, but this approach is accompanied by a reduction in statistical power for detecting carcinogenic potential. The present study was conducted to evaluate the loss of power associated with early termination. Data from drug studies in rats were used to formulate biologically based dose-response models of carcinogenesis using the 2-stage clonal expansion model as a context. These dose-response models, which were chosen to represent 6 variations of the initiation-promotion-completion cancer model, were employed to generate a large number of representative bioassay data sets using Monte Carlo simulation techniques. For a variety of tumor dose-response trends, tumor lethality, and competing risk-survival rates, the power of age-adjusted statistical tests to assess the significance of carcinogenic potential was evaluated at 18 and 21 months, and compared to the power at the normal 24-month stopping time. The results showed that stopping at 18 months would reduce power to an unacceptable level for all 6 submodels of the 2-stage clonal expansion model, with the pure-promoter and pure-completer models being most adversely affected. For the 21-month stopping time, the results showed that, unless pure promotion can be ruled out a priori as a potential carcinogenic mode of action, the loss of power is too great to warrant early stopping. (+info)
Novelties in the field of anti-infective compounds in 1999.
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In 1999 the number of new compounds reported in the anti-infective field decreased significantly in comparison with previous years, especially for antifungals. The reported new compounds are mainly directed against Staphylococcus aureus isolates resistant to methicillin. Few derivatives were reported in the field of anti-infectives for gram-negative bacteria. At the moment, we are in a period of discovery as we await novel compounds that could issue from new engineering. (+info)
Development of matrix metalloproteinase inhibitors in cancer therapy.
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The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in the processes of tumor growth, invasion, and metastasis; are frequently overexpressed in malignant tumors; and have been associated with an aggressive malignant phenotype and adverse prognosis in patients with cancer. A number of MMP inhibitors are being developed for the treatment of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP active site, tetracycline derivatives, and bisphosphonates. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the MMP-active site, were the first MMP inhibitors to be studied in detail. Marimastat is currently being studied in randomized clinical trials. The nonpeptidic MMP inhibitors were synthesized in an attempt to improve the oral bioavailability and pharmaceutical properties of the peptidic inhibitors. Several members of this class of compounds are undergoing evaluation in phase III clinical trials. The tetracyclines and, particularly, the nonantibiotic chemically modified tetracyclines, interfere with several aspects of MMP expression and activation and inhibit tumor growth and metastases in preclinical models. A representative agent of this class, Col-3, is currently undergoing phase I clinical trials. The development of the MMP inhibitors, like that of other targeted and predominantly antiproliferative compounds, poses a challenge because the paradigms that have governed the design of clinical oncology trials may not be relevant to this new class of agents. The anticipated need for long-term administration of these drugs, together with their cytostatic mechanism of action, will require novel clinical trial design strategies. (+info)
From anatomy to the target: contributions of magnetic resonance imaging to preclinical pharmaceutical research.
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In recent years, in vivo magnetic resonance (MR) methods have become established tools in the drug discovery and development process. In this article, the role of MR imaging (MRI) in the preclinical evaluation of drugs in animal models of diseases is illustrated on the basis of selected examples. The individual sections are devoted to applications of anatomic, physiologic, and "molecular" imaging providing, respectively, structural-morphological, functional, and target-specific information. The impact of these developments upon clinical drug evaluation is also briefly addressed. The main advantages of MRI are versatility, allowing a comprehensive characterization of a disease state and of the corresponding drug intervention; high spatial resolution; and noninvasiveness, enabling repeated measurements. Successful applications in drug discovery exploit one or several of these aspects. Additionally, MRI is contributing to strengthen the link between preclinical and clinical drug research. (+info)
A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis.
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Standard therapy in the United States for malignancy-associated hyperuricemia consists of hydration, alkalinization, and allopurinol. Urate oxidase catalyzes the enzymatic oxidation of uric acid to a 5 times increased urine soluble product, allantoin. Rasburicase is a new recombinant form of urate oxidase available for clinical evaluation. This multicenter randomized trial compared allopurinol to rasburicase in pediatric patients with leukemia or lymphoma at high risk for tumor lysis. Patients received the assigned uric acid-lowering agent for 5 to 7 days during induction chemotherapy. The primary efficacy end point was to compare the area under the serial plasma uric acid concentration curves during the first 96 hours of therapy (AUC(0-96)). Fifty-two patients were randomized at 6 sites. In an intent-to-treat analysis, the mean uric acid AUC(0-96) was 128 +/- 70 mg/dL.hour for the rasburicase group and 329 +/- 129 mg/dL.hour for the allopurinol group (P <.0001). The rasburicase versus allopurinol group experienced a 2.6-fold (95% CI: 2.0-3.4) less exposure to uric acid. Four hours after the first dose, patients randomized to rasburicase compared to allopurinol achieved an 86% versus 12% reduction (P <.0001) of initial plasma uric acid levels. No antirasburicase antibodies were detected at day 14. This randomized study demonstrated more rapid control and lower levels of plasma uric acid in patients at high risk for tumor lysis who received rasburicase compared to allopurinol. For pediatric patients with advanced stage lymphoma or high tumor burden leukemia, rasburicase is a safe and effective alternative to allopurinol during initial chemotherapy. (+info)
Developmental therapeutics program at the NCI: molecular target and drug discovery process.
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As the drug discovery and developmental arm of the National Cancer Institute (NCI), the Developmental Therapeutics Program (DTP) plans, conducts and facilitates development of therapeutic agents for cancer and AIDS. DTP's goal is to turn 'molecules into medicine for the public health'. Areas of support by DTP are discovery, development and pathways to development for the intramural and the extramural community. The Developmental Therapeutics Program (DTP) operates a repository of synthetic and pure natural products, which are evaluated as potential anticancer agents. The repository derives from a historical database of greater than 600 000 compounds, which have been supplied to DTP from a variety of sources worldwide. The in vitro anti-cancer drug cell line screen established at DTP is unique in several respects. It has changed the NCI emphasis from a compound-oriented drug discovery effort to a disease-panel oriented exercise, emphasized human tumor cells derived from solid tumors, developed a high volume screening method that can adapt to processing of numerous chemical agents or natural source-derived extracts, that has minimized the use of animals, and saved on the amount of material required for the initial screening. The hollow fiber assay created at the DTP has demonstrated the ability to provide quantitative initial indices of in vivo drug efficacy, with minimum expenditures of time and materials and is currently being utilized as the initial in vivo experience for agents found to have reproducible activity in the in vitroanticancer drug screen. Drugs showing activity with unique mechanisms of actions are being further developed for treatment of hematopoietic neoplasms, prominent examples being flavopiridol, UCN-01 and depsipeptide among others. (+info)