Potential new drugs are assessed in pre-clinical in vivo studies to determine their safety profiles. The drugs are formulated in vehicles suitable for the route of administration and the physicochemical properties of the drug, aiming to achieve optimal exposure in the test species. The availability of safety data on vehicles is often limited (incomplete data, access restricted/private databases). Nineteen potentially useful vehicles that contained new and/or increased concentrations of excipients and for which little safety data have been published were tested. Vehicles were dosed orally once daily to HanWistar rats for a minimum of 28 days and a wide range of toxicological parameters were assessed. Only 30% (w/v) hydroxypropyl-ß-cyclodextrin was found unsuitable owing to effects on liver enzymes (AST, ALT and GLDH), urinary volume and the kidneys (tubular vacuolation and tubular pigment). 20% (v/v) oleic acid caused increased salivation and hence this vehicle should be used with caution. As 40% (v/v) tetraethylene glycol affected urinary parameters, its use should be carefully considered, particularly for compounds suspected to impact the renal system and studies longer than 1 month. There were no toxicologically significant findings with 10% (v/v) dimethyl sulphoxide, 20% (v/v) propylene glycol, 33% (v/v) Miglyol®812, 20% (w/v) Kolliphor®RH40, 10% (w/v) Poloxamer 407, 5% (w/v) polyvinylpyrrolidone K30 or 10% (v/v) Labrafil®M1944. All other vehicles tested caused isolated or low magnitude effects which would not prevent their use. The aim of sharing these data, including adverse findings, is to provide meaningful information for vehicle selection, thereby avoiding repetition of animal experimentation.
The second case of magA+ rmpA+ hypermucoviscosity phenotype Klebsiella pneumoniae infection was documented in Canada, in an immigrant from Algeria. To ascertain whether this represented recent importation of the strain or local transmission within Canada, a retrospective study of K. pneumoniae bacteraemia was conducted in the region, from 1997 to 2007, and 411 episodes were identified. No epidemiological evidence for local transmission of this strain was found. However, for the first time, the population incidence of K. pneumoniae bacteraemia was determined, which increased by 82% between 1997 and 2007, from 10.2 to 18.7 per 100 000 inhabitants. Incidence increased dramatically with age and with the presence of diabetes, but remained stable over time within each stratum. The proportion of patients with K. pneumoniae bacteraemia who were diabetic increased from 26% (1997-2004) to 42% (2005-2007). The rising incidence of K. pneumoniae bacteraemia may represent an unexpected consequence of the expanding population of adult diabetics.
Current clinical poly (ADP-ribose) polymerase (PARP) inhibitors target both PARP1 and PARP2 and they all cause clinical cytopenias with varying severity. Understanding the mechanism underlying the hematological toxicity of these agents is key for the rational design of a best-in-class molecule with greater therapeutic potential, both as monotherapy and in combination with chemotherapy. We validated the rat as a physiologically competent translational model to investigate PARP inhibitor-driven hematological toxicity. Here we demonstrate that in comparison with a representative PARP1/2 inhibitor, olaparib, the novel highly potent PARP1-selective inhibitor and trapper, AZD5305, does not cause hematological toxicity as a monotherapy in pre-clinical rat models at predicted clinically efficacious exposures. Thus, monotherapy toxicity of PARP1/2 inhibitors likely depends on PARP2 inhibition. Next, we proceeded to investigate whether PARP1-selective inhibition would be better tolerated in chemotherapy combinations than PARP1/2 inhibition. We performed a rat in vivo study comparing daily olaparib or daily AZD5305 at matched exposures in combination with one cycle of intravenous carboplatin for 14 days. We show that olaparib and PARP1-selective AZD5305 cause comparable exacerbation of carboplatin-induced peripheral blood effects implicating PARP1 inhibition in combination-driven hematological toxicity. Importantly however, AZD5305+carboplatin showed improved hematological tolerability over olaparib+carboplatin because peripheral reticulocytes and bone marrow erythroid precursor cells recover in the presence of continuous AZD5305 but not in the presence of continuous olaparib. Importantly, this differentiation was maintained in a subsequent rat in vivo study, where daily olaparib or daily AZD5305 were combined with two three-weekly cycles of a higher dose of carboplatin to more closely mimic clinical protocol. AZD5305+carboplatin was associated with a more rapid recovery of reticulocytes, red blood cells and hemoglobin following both cycles of carboplatin. In contrast, olaparib+carboplatin was associated with a slower recovery resulting in a more sustained reduction in red cells and hemoglobin during both the first and second cycle of carboplatin. Thus, in rodents the novel potent PARP1-selective inhibitor AZD5305 has improved hematological tolerability over dual PARP1/2 inhibitors, both as a monotherapy and in carboplatin combinations. Citation Format: Sonja J. Gill, Ruth Macdonald, Carmen Pin, Rob Collins, Emilyanne Leonard, Gareth Maglennon, Andy Pike, Peter Cotton, Glen Hawthorne, Jordan Pugh, Rebecca Sargeant, Daniel Sutton, James Atkinson, Stewart Jones, Sarah Chinery, Mark Anderton. The novel PARP1-selective inhibitor AZD5305 has reduced hematological toxicity when compared to PARP1/2 inhibitors in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1374.
A novel selective glucocorticoid receptor (GR) agonist, AZD2906, was found to increase the incidence of micronucleated immature erythrocytes (MIE) in the bone marrow of rats given two oral doses at the maximum tolerated level. Because GR agonists as a class are considered not to be genotoxic and AZD2906 showed no activity in the standard in vitro tests or in vivo in a rat liver comet assay, investigative studies were performed to compare AZD2906 with a reference traditional GR agonist, prednisolone. Emphasis was placed on blood and bone marrow parameters in these studies because GR activation has been reported to induce erythropoiesis which, in turn, is known to increase MIE in the bone marrow. Both compounds induced almost identical, small increases in micronucleus frequency at all doses tested. Directly comparable changes in haematological and bone marrow parameters were also seen with significant decreases in lymphoid cells in both compartments and significant increases in numbers of circulating neutrophils. Although no evidence of increased erythropoiesis was seen as increased immature erythrocyte numbers either in the blood or in the bone marrow, histopathological examination showed focal areas in the bone marrow where the erythroid population was enriched in association with an atrophic myeloid lineage. This could have been due to direct stimulation of the erythroid lineage or a secondary effect of myelosuppression inducing a rebound increase in erythropoiesis into the vacant haematopoietic cell compartment. It was concluded that the increased MIE frequencies induced by both AZD2906 and prednisolone are a consequence of their pharmacological effects on the bone marrow, either by directly inducing erythropoiesis or by some other unknown effect on cellular function, and do not indicate potential genotoxicity. This conclusion is supported by the lack of carcinogenic risk in man demonstrated by decades of clinical use of prednisolone and other GR agonists.
Severe COVID-19 can be associated with a prothrombotic state, increasing risk of morbidity and mortality. The SARS-CoV-2 spike glycoprotein is purported to directly promote platelet activation via the S1 subunit and is cleaved from host cells during infection. High plasma concentrations of S1 subunit are associated with disease progression and respiratory failure during severe COVID-19. There is limited evidence on whether COVID-19 vaccine-induced spike protein is similarly cleaved and on the immediate effects of vaccination on host immune responses or hematology parameters. We investigated vaccine-induced S1 subunit cleavage and effects on hematology parameters using AZD1222 (ChAdOx1 nCoV-19), a simian, replication-deficient adenovirus-vectored COVID-19 vaccine. We observed S1 subunit cleavage in vitro following AZD1222 transduction of HEK293x cells. S1 subunit cleavage also occurred in vivo and was detectable in sera 12 hours post intramuscular immunization (1x1010 viral particles) in CD-1 mice. Soluble S1 protein levels decreased within 3 days and were no longer detectable 7–14 days post immunization. Intravenous immunization (1x109 viral particles) produced higher soluble S1 protein levels with similar expression kinetics. Spike protein was undetectable by immunohistochemistry 14 days post intramuscular immunization. Intramuscular immunization resulted in transiently lower platelet (12 hours) and white blood cell (12–24 hours) counts relative to vehicle. Similarly, intravenous immunization resulted in lower platelet (24–72 hours) and white blood cell (12–24 hours) counts, and increased neutrophil (2 hours) counts. The responses observed with either route of immunization represent transient hematologic changes and correspond to expected innate immune responses to adenoviral infection.
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