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At least 19 recordsLinked to original sources
PubMed1978

Preclinical safety evaluation of 15[S]15-methyl prostaglandin F2alpha : reproduction and teratology.

The abortifacient 15[S]15-methyl prostaglandin F2alpha, designated PGF2alpha (M), was tested in pregnant rats and rabbits for purposes of preclinical safety evaluation. The material tested was the tromethamine salt of PGF2alpha with the generic name, carboprost tromethamine. Doses of 0.25, 0.50, and 1 mg/kg given by subcutaneous injection to male and female rats for 3 or 6 consecutive days before mating did not have an adverse effect on reproduction. The principal finding in rat and rabbit teratology studies was that PGF2alpha (M) had a high order of embryolethality regardless of when it was administered. Rabbits were more sensitive than were rats and PGF2alpha (M) interfered with nidation or early embryonic development when given during the second week of gestation. The largest dose of PGF2alpha (M) that allowed some fetuses to survive was 0.25 mg/kg for rats and 0.005 mg/kg for rabbits when given by subcutaneous injection for 3 consecutive days at some point during organogenesis. Fetuses from rabbits given the doses of 0.0025 and 0.005 mg/kg were normal. There were a variety of skeletal anomalies (mostly of ribs and thoracic vertebrae) in fetuses from rats given, by subcutaneous injection, doses of PGF2alpha (M) ranging from 0.25 to 0.05 mg/kg for 3 consecutive days at some point during organogenesis. Although there were few gross or visceral anomaliies in either rats or rabbits, the incidence of osseous anomalies in rats was of both statistical and biologic significance. Rats given PGF2alpha (M) by subcutaneous injection beginning on the 15th day of gestation in a perinatal-postnatal study were most sensitive to the abortifacient. In that study the no-effect level was 0.0001 mg/kg. At larger doses ranging from 0.25 to 0.003 mg/kg, treatment was associated with abortion, poor viability, and impaired lactation.

Abnormalities, Drug-Induced↗
PubMed1992

The preclinical safety evaluation of human monoclonal antibody against cytomegalovirus.

The human monoclonal antibody against cytomegalovirus (Mab C23) was examined pharmacokinetically and toxicologically as part of the preclinical studies prior to approval for human use. Rats given repeated intravenous administrations of Mab C23 produced no antibodies against Mab C23 and maintained a blood Mab C23 level in a dose-dependent manner. However, pregnant rabbits produced antibodies against Mab C23. The half-life of Mab C23 in plasma was 15.9 days in rats, which was similar to that of normal human serum gamma-globulin (NHSG). Neither behavioral effects nor circulatory disturbance was found in mice, rats, and dogs even after a single intravenous injection of 100 or 200 mg/kg, which corresponds to 50 or 100 times the intended clinical dosage. The repeated doses of 2, 10, or 20 mg/kg of Mab C23 on six occasions with 1- or 2-week intervals elicited a transient decrease in leukocyte counts in rats given 10 or 20 mg/kg, but no adverse effects in cynomolgus monkeys. Mab C23 did not cause any reproductive or developmental toxicity when administered to rats and rabbits at dose levels of 20 mg/kg or less. However, pregnant animals showed lower plasma levels of Mab C23 than non-pregnant animals. The chromosomal aberration test disclosed no clastogenicity in human lymphocytes. An immunostaining for Mab C23 revealed no localizations in several tissues of cynomolgus monkeys given intravenous doses of Mab C23.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Preclinical safety evaluation of dilevalol (SCH 19927), an antihypertensive agent, in the rat.

Dilevalol (SCH 19927) is an antihypertensive agent with direct vasodilating properties due to beta 2-adrenergic receptor agonist activity and nonselective beta-receptor blocking activity. In acute (single dose) oral and parenteral studies a low order of toxicity was observed. Clinical signs observed at the higher doses included salivation, prostration, tremors, and convulsions. In multidose oral studies dilevalol produced an increase in mean absolute and/or relative heart weights observed as early as 1 month in the high-dose (300 mg/kg) rats and at all dose levels (35, 90, 220 mg/kg) in rats treated for 1 year. There were no microscopic changes that could be associated with the change in heart weight. Intraalveolar macrophages were observed in the lung tissue of rats treated for 3 months or 1 year with an increase in relative lung weights noted in the high-dose (220 mg/kg) group treated for 1 year. In a 2-year rat study, no evidence of oncogenicity was observed. On the basis of these studies, dilevalol has a low order of toxicity and lacks oncogenic potential in the rat.

Animals↗
PubMed1992

Enzymology in preclinical safety evaluation.

This short paper will briefly discuss the merits of determining plasma enzyme activities in pre-clinical safety evaluation. Emphasis is placed on the value of selecting the appropriate enzymes and collecting blood samples at the appropriate times during the study, so as to gain the maximum amount of diagnostic information. Examples of actual results will be cited to illustrate some of the points. These examples are drawn from the 2 commonly used toxicology species--the laboratory white rat and the beagle--and serve to demonstrate the importance of enzymology in monitoring the progress or resolution of an adverse drug effect.

Animals↗
PubMed1992

Summary of preclinical safety evaluation of gadoteridol injection.

RATIONALE AND OBJECTIVES: To support clinical use of gadoteridol (0.5 M) injection, a battery of in vitro and in vivo safety studies was conducted. RESULTS: In mice, the acute intravenous LD50 for gadoteridol (0.5 M) injection was 11 to 14 mmol/kg, and the intravenous minimal lethal dose in rats was greater than 10 mmol/kg. In 2-week studies with gadoteridol, no serious effects were observed in mice given 3 mmol/kg or dogs given 1.5 mmol/kg daily. In a series of reproduction studies, no treatment-related adverse effects on fertility, reproductive performance, or postnatal development were seen in rats at doses of 1.5 mmol/kg or less, and no teratogenic effects were observed at doses as high as 6 mmol/kg in rabbits and 10 mmol/kg in rats. In an in vitro test, gadoteridol did not demonstrate any potential to hemolyze human erythrocytes when incubated in high concentrations with whole blood, suggesting there is little probability gadoteridol will cause hemolysis in vivo. CONCLUSIONS: A substantial margin of safety exists for the clinical use of gadoteridol in magnetic resonance imaging procedures.

Abnormalities, Drug-Induced↗
PubMed1992

A sequential multi-assay protocol for the preclinical assessment of natural product complex carbohydrate immunomodulators.

A major barrier to the understanding, development and utilization of natural product complex carbohydrate immunomodulators has been the lack of standardization during pre-clinical efficacy and safety testing. In addition, it has been our experience that no single assay system or model is adequate for assessing preclinical efficacy and safety of these agents. To address these important issues, our laboratory group has developed a sequential multi-assay protocol for the preclinical evaluation of natural product complex carbohydrate immunomodulators. This sequential multi-assay screening protocol is divided into four phases: 1) physiochemical characterization of the carbohydrate polymer; 2) evaluation of immune stimulatory activity; 3) assessing in vivo anti-microbial activity and anti-tumor efficacy and 4) preclinical safety evaluation. This sequential protocol provides an effective, reproducible and rational approach to the preclinical assessment of complex carbohydrate immunomodulators that, in our experience, is predictive of clinical safety and efficacy.

Adjuvants, Immunologic↗
PubMed2026

Pre-clinical immunogenicity and safety evaluation of H2 strain Hepatitis A Inactivated Vaccine in rhesus macaques.

BACKGROUND: Hepatitis A is a viral infection of the liver that can cause mild to severe illness. Currently, two types of HAV vaccines are used worldwide, inactivated hepatitis A vaccines, which are used in most countries, and live attenuated vaccines (H2 and L-A-1 strain), which are mainly used in China. The major disadvantage of live attenuated virus to cause secondary infections among contacts and mutation shifts of the live vaccine strain. The H2 strain was selected for the development of an inactivated hepatitis A vaccine to further reduce biosafety risks. Rhesus macaques high genomic homology with humans and the incubation period after hepatitis A vaccination and human natural infections are similar. We use rhesus macaques to assess immunogenicity and safety of the H2 strain Hepatitis A Inactivated Vaccine. METHODS: The vaccine was assessed in rhesus macaques, divided into four groups (n = 10 per group): the control group (adjuvant buffer; aluminum content 0.35 mg/mL; 2 mL per dose), the low-dose group (320EU, 0.5 mL of 640EU/mL with aluminum content 0.35 mg/mL), the medium-dose group (640EU, 1 mL of 640EU/mL with aluminum content 0.35 mg/mL), and the high-dose group (1280EU, 2 mL of 640EU/mL with aluminum content 0.35 mg/mL). Animals were injected intramuscularly at multiple sites in the hind limbs and received four inoculations at 4-week intervals. Test items including Clinical indicators, immunogenicity indicators and Histopathological examination. RESULTS: No abnormalities were observed in any group in terms of general clinical condition throughout the study period except for slight decreases in body temperature after immunization. Hematological parameters, serum biochemistry indices, and histopathological findings showed fluctuated to different degrees of fluctuation after immunization across all groups. Immunogenicity assessments showed that the inactivated hepatitis A vaccine (H2) induced both humoral and cellular immune responses effectively, and the levels of antibodies increased with certain dose- and time-response trends. CONCLUSION: The inactivated hepatitis A vaccine (H2 strain, human diploid cell) was safe and immunogenic in non-human primates. The results provide strong preclinical support for the further clinical development of this vaccine candidate.

Animals↗
PubMed2026

Single-cell vector copy number analysis of phenotypically defined long-term hematopoietic stem cells for gene therapy safety assessment.

Hematopoietic stem cell (HSC)-based gene therapy has emerged as a transformative approach for the treatment of genetic diseases; however, accurate evaluation of vector copy number (VCN) remains critical for ensuring safety. Conventional bulk VCN assays, including quantitative PCR (qPCR) and droplet digital PCR (ddPCR), do not resolve clonal heterogeneity and cannot identify rare high-VCN cells that may contribute disproportionately to insertional mutagenesis risk. Here, we developed an accessible single-cell VCN profiling method by combining fluorescence-activated cell sorting (FACS) of phenotypically defined long-term HSCs (Lineage- CD34+ CD38- CD90+ CD45RA- cells) with whole-genome amplification followed by conventional qPCR. This approach enabled resolution of VCN distributions at single-cell level using standard laboratory techniques. Notably, single-cell analysis revealed a high VCN tail that bulk VCN analysis could not resolve. Furthermore, in a humanized mouse transplantation model, single-cell VCN profiling demonstrated that overall VCN distributions could be analyzed after engraftment, although inter-donor and inter-mouse variability was observed. Collectively, this method provides a rapid, cost-effective, and phenotypically resolved strategy for assessing VCN heterogeneity in gene-modified HSCs. Single-cell VCN profiling offers complementary insights beyond conventional bulk assays and may enhance preclinical safety evaluation of gene and cell therapy products.

lentiviral vector↗
PubMed1992

The status of eye irritancy testing: a regulatory perspective.

Eye irritation testing is a salient public issue and continues to escalate on the public agenda. Issues relevant to this milieu include legislative proposals to ban animal use for cosmetic testing, adequacy of the current standard (viz., the Draize Eye Irritancy Test), availability of non-animal methodologies, validation paradigm for new testing models, international harmonization of testing standards and methods, and the regulatory role in product testing and enforcement. The Food and Drug Administration (FDA) feels that enactment of legislation proposed to ban animal use from testing products for safety would pose serious problems from a public health perspective. FDA encourages the development of alternative test methods and is aware that many such tests are in various stages of evolution. At this time, however, none of these tests has been accepted by the scientific community as total replacement to the Draize test. FDA's basic positions on the use of non-animal alternatives are as follows: 1) The use of animal tests by industry to establish the safety of regulated products is necessary to minimize the risks from such products to humans, 2) The Draize eye irritancy test is currently the most valuable and reliable method for evaluating the hazard or safety of a substance introduced into or around the human eye, and 3) No non-animal tests are presently available to completely replace the Draize. FDA is actively involved with U.S. and international groups to harmonize protocols for product development, evaluate the current status of non-whole animal methodologies, and standardize testing requirements. The Agency has recently participated in several scientific symposia evaluating the status of non-whole animal methods in toxicity testing. Moreover, FDA representatives are currently scheduled to participate in international meetings and workshops planned for the immediate future addressing several issues in product safety determination.

Animal Testing Alternatives↗
PubMed1992

Utilization of homologous proteins to evaluate the safety of recombinant human proteins--case study: recombinant human interferon-gamma (rhIFN-gamma).

Interferon-gamma is an immunomodulatory cytokine that has an extremely restricted host range of activities. RhIFN-gamma was one of the first species-specific recombinant proteins to be assessed in conventional safety models typically utilized for xenobiotics. Acute, subchronic and Segment I and II reproductive studies in rats revealed no evidence of toxicity at any of the doses tested; these results were not predictive of clinical toxicity, which is not unexpected since rodents are known to be pharmacologically nonresponsive to rhIFN-gamma. In contrast, 4- and 13-week multidose toxicity studies in cynomolgus monkeys with rhIFN- were predictive of many of the dose-limiting clinical toxicities. RhIFN- is active on non-human primate cells, though not at the same level as on human cells. In addition, qualitative similarities were observed between toxicity studies employing rhIFN-gamma in the cynomolgus monkey and recombinant murine interferon-gamma (rmuIFN-gamma) in the mouse. These results suggest that in situations where a high degree of species specificity is encountered, studies employing a recombinant protein in a homologous species may provide a useful test system for preclinical safety assessment. This information should be evaluated in conjunction with data from studies conducted with the human protein in pharmacologically responsive animal models when possible.

Animals↗
PubMed1992

Differential analysis of animal bone marrow by flow cytometry.

A simple procedure was developed for rapid analysis of animal bone marrow by flow cytometry using the lipophilic cationic dye 3,3'-dihexyloxacarbocyanine iodide [DiOC6(3)]. The batch process allows differentiation of bone marrow cells into lymphoid, erythroid, and myeloid populations and enables classification of erythroid and myeloid cells into proliferating and maturing subpopulations. From these data, myeloid:erythroid (M:E) ratios and maturation indices for erythroid and myeloid cells (EMI and MMI, respectively) can be derived. This procedure provides the opportunity to analyze bone marrow quantitatively and offers distinct advantages to current manual methods in terms of simplicity, throughput, and reproducibility. The method has been tested successfully using marrow from Wistar rats, B6C3F1 mice, beagle dogs, and cynomolgus monkeys. This technique facilitates the evaluation of bone marrow samples taken from preclinical safety studies or from animal colonies of large size.

Animals↗