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David Jacobson-Kram

Publications and source records attributed to David Jacobson-Kram.

10 recordsLinked to original sources
PubMed2006

Genetic toxicity assessment: employing the best science for human safety evaluation. Part I: Early screening for potential human mutagens.

Results of genetic toxicology tests are used by FDA's Center for Drug Evaluation and Research as a surrogate for carcinogenicity data during the drug development process. Mammalian in vitro assays have a high frequency of positive results which can impede or derail the drug development process. To reduce the risk of such delays, most pharmaceutical companies conduct early non-GLP (good laboratory practices) studies to eliminate drug candidate with mutagenic or clastogenic activity. Early screens include in silico structure activity assessments and various iterations of the ultimate regulatory mandated GLP studies.

Animals↗
PubMed2006

Toxicological overview of impurities in pharmaceutical products.

While the use of pharmaceuticals is always a balance of risks and benefits, the same is not true for impurities in pharmaceuticals; impurities convey only risk. A number of international guidelines and regional guidances instruct drug developers and regulatory agencies on how to evaluate and control impurities in drug substances and drug products. While impurities should always be reduced to the lowest levels that are reasonably practical, it is acknowledged that impurities cannot be reduced to zero and specifications for impurities need to be established. This chapter discusses practical and theoretical methods for qualification of different classes of impurities.

Drug Contamination↗
PubMed2005

Biological monitoring and surveillance results of Gulf War I veterans exposed to depleted uranium.

OBJECTIVE: To relate medical surveillance outcomes to uranium biomonitoring results in a group of depleted uranium (DU)-exposed, Gulf War I veterans. METHODS: Thirty-two veterans of Gulf War I who were victims of 'friendly fire' involving DU weapons, in whom exposure assessment can accurately be measured, had urine uranium concentrations determined using ICP-MS technology. Clinical laboratory parameters were measured and related to urine uranium concentrations. Data were examined by stratifying the cohort into a low U group, <0.10 mug/g creatinine versus a high U group, >/=0.10 mug/g creatinine and assessing differences between groups. RESULTS: Over a decade after first exposure, soldiers possessing embedded DU fragments continue to excrete elevated concentrations of uranium in urine. No clinically significant uranium related health effects were observed in blood count, blood chemistries including renal markers, neuropsychological measures, and semen quality or genotoxicity measures. Markers of early changes in renal glomerular and tubular function were not statistically different between groups; however, genotoxicity measures continue to show subtle, mixed results. CONCLUSION: Persistent urine uranium elevations continue to be observed more than 12 years since first exposure. Despite this, renal and other clinical abnormalities were not observed, likely due to the 'relatively' low uranium burden in this cohort compared to historical uranium-exposed occupational groups. Continuing surveillance is indicated, however, due to the on-going nature of the exposure. These results are an important finding in light of the on-going controversy regarding health effects observed in soldiers of the Gulf War and other conflicts, whose uranium exposure assessment is unable to be accurately determined.

Adolescent↗
PubMed2004

Human carcinogenic risk evaluation, Part III: Assessing cancer hazard and risk in human drug development.

Assessing cancer risk for human pharmaceuticals is important because drugs are taken at pharmacologically active doses and often on a chronic basis. Epidemiologic studies on patient populations have limited value because of the long latency period for most cancers and because these studies lack sensitivity. The Center for Drug Evaluation and Research (CDER) of the U.S. Food and Drug Administration relies on short-term surrogate assays (genetic toxicology studies) to assess risk to patients involved in clinical trials and on rodent carcinogenicity studies to assess cancer risk for drug approval. Unlike some other agencies that typically perform quantitative risk assessments on chemical pollutants or pesticide products, CDER does not perform such quantitative extrapolations. Rather, the evaluation of risk is the result of an integrated assessment of what is known about the drug, and risk is considered in the context of the clinical benefit. Mode of action of carcinogenesis and thresholds for effects are important considerations. The results of carcinogenicity studies of approved products are published in the drug labeling and individual clinicians balance risk and benefit in making prescribing decisions.

Animals↗
PubMed2004

Health effects of depleted uranium on exposed Gulf War veterans: a 10-year follow-up.

Medical surveillance of a group of U.S. Gulf War veterans who were victims of depleted uranium (DU) "friendly fire" has been carried out since the early 1990s. Findings to date reveal a persistent elevation of urine uranium, more than 10 yr after exposure, in those veterans with retained shrapnel fragments. The excretion is presumably from ongoing mobilization of DU from fragments oxidizing in situ. Other clinical outcomes related to urine uranium measures have revealed few abnormalities. Renal function is normal despite the kidney's expected involvement as the "critical" target organ of uranium toxicity. Subtle perturbations in some proximal tubular parameters may suggest early although not clinically significant effects of uranium exposure. A mixed picture of genotoxic outcomes is also observed, including an association of hypoxanthine-guanine phosphoribosyl transferase (HPRT) mutation frequency with high urine uranium levels. Findings observed in this chronically exposed cohort offer guidance for predicting future health effects in other potentially exposed populations and provide helpful data for hazard communication for future deployed personnel.

Adult↗
PubMed2003

Distribution and toxicity resulting from adenoviral vector administration to a single salivary gland in adult rats.

BACKGROUND: We examined the distribution and toxicity associated with a single salivary gland administration of a recombinant adenoviral vector, AdCMVH3, encoding human histatin 3. METHODS: Adult rats received different doses of AdCMVH3 (0, 106, 3 x 107, and 109 pfu; 50 microl) via the right submandibular gland and were followed for 15 days. Food consumption, weight gain, clinical appearance, and serum chemistry were monitored, and a necropsy was performed. Vector distribution was examined by polymerase chain reaction, and selected saliva samples were tested for replication-competent adenovirus (RCA). RESULTS: All animals survived to sacrifice (days 2, 8, and 15), and appeared normal clinically. There were no differences in food consumption, weight gain, and serum chemistry. The only consistent necropsy findings were lymphoid infiltrates and necrosis in the target submandibular glands of high-dosage animals. AdCMVH3 detection was virus dose dependent, decreased with time, and at low dose preferentially observed in the targeted gland. No RCA was detected. CONCLUSIONS: Salivary gland administration of 109 pfu AdCMVH3 elicits an initial focal pathologic response and wide tissue distribution. There is no associated systemic toxicity up to 15 days, and lower doses are primarily found in glands.

Adenoviridae↗
PubMedDate not supplied

Use of transgenic mice in carcinogenicity hazard assessment.

Determining the carcinogenic potential of materials to which humans have significant exposure is an important, complex and imperfect exercise. Not only are the methods for such determinations protracted, expensive and utilize large numbers of animals, extrapolation of data from such studies to human risk is imprecise. Toxicologists have long recognized these shortcomings but the 2-year chronic rodent study has remained the gold standard. Recent developments in the field of molecular oncology and development of methods to insert or inactivate specific genes in animals have provided the tools with which to develop the next generation of carcinogenicity assays. With improved understanding of oncogene activation and tumor suppressor gene inactivation a number of animal models have been developed to dramatically reduce latency for chemically induced cancers. This has led to the development of shorter carcinogenicity assays. Also, because the spontaneous tumor frequencies in these animals are low during the in-life portion of the study, and studies are terminated well before the health complications of advanced aging are observed, it has been possible to reduce the group sizes and reduce animal usage. FDA's adoption of ICH S1B in 1997, (ICH, 1997) "Testing for the Carcinogenicity of Pharmaceuticals," opened the door for the use of such transgenic models in regulatory toxicology. This presentation reviews the current state of the science and its application to regulatory issues.

Animals↗
PubMedDate not supplied

Use of genotoxicity data to support clinical trials or positive genetox findings on a candidate pharmaceutical or impurity .... now what?

Results from carcinogenicity studies are generally not available for drugs until the time of approval. Many people, including healthy volunteers are often exposed to pharmacologically active doses of the drug before carcinogenicity results are available. The Food and Drug Administration (FDA) Center for Drug Evaluation and Research uses results of genetic toxicology studies as a surrogate for carcinogenicity during the drug development phase (clinical trials). A number of issues are considered in deciding whether drugs that give positive results in genetic toxicology studies can be given to subjects in clinical trials. These relate to the drug indication, the target population, duration of treatment, and importance of the drug. In general, single-dose clinical studies are permitted regardless of the genetox results. In situations where a genetic toxicology assay showed a positive result, some review divisions have asked sponsors to perform a Syrian hamster embryo (SHE) cell transformation assay or a p53 carcinogenicity study prior to allowing repeat-dose clinical trials to proceed. This paper discusses alternatives to SHE cell and p53 assays when faced with a positive result in a genetic toxicology assay. In addition, this paper discusses factors to consider when setting limits for genotoxic impurities in drug substances and products.

Animals↗