Despite six decades of clinical experience with the polymyxin class of antibiotics, their dose-limiting nephrotoxicity remains difficult to predict due to a paucity of sensitive biomarkers. Here, we evaluate the performance of standard of care and next-generation biomarkers of renal injury in the detection and monitoring of polymyxin-induced acute kidney injury in male Han Wistar rats using colistin (polymyxin E) and a polymyxin B (PMB) derivative with reduced nephrotoxicity, PMB nonapeptide (PMBN). This study provides the first histopathological and biomarker analysis of PMBN, an important test of the hypothesis that fatty acid modifications and charge reductions in polymyxins can reduce their nephrotoxicity. The results indicate that alterations in a panel of urinary kidney injury biomarkers can be used to monitor histopathological injury, with Kim-1 and α-GST emerging as the most sensitive biomarkers outperforming clinical standards of care, serum or plasma creatinine and blood urea nitrogen. To enable the prediction of polymyxin-induced nephrotoxicity, an in vitro cytotoxicity assay was employed using human proximal tubule epithelial cells (HK-2). Cytotoxicity data in these HK-2 cells correlated with the renal toxicity detected via safety biomarker data and histopathological evaluation, suggesting that in vitro and in vivo methods can be incorporated within a screening cascade to prioritize polymyxin class analogs with more favorable renal toxicity profiles.
1 A gamma scintigraphic study has been carried out on the precorneal residence and pharmacodynamic action of a radiolabelled New Ophthalmic Delivery System (NODS) containing pilocarpine nitrate in 12 healthy volunteers. 2 The NODS was radiolabelled with the soluble marker technetium-99m labelled diethylenetriaminepentaacetic acid, to mark the release characteristics of soluble drugs contained within the matrix. 3 The relationship between the precorneal residence time of the marker and the duration of drug effect on intraocular pressure and pupil diameter was monitored.Results obtained following administration of the NODS were compared with those obtained after administration of a 25 RI drop of a 2% w/v pilocarpine nitrate solution.Each formulation was administered to one eye only, the other eye acting as a control. 4 Dissolution of the radiolabel from the NODS in vivo showed considerable intersubject variation with half-times of dissolution ranging from 46 s to 833 s (mean ± s.d. -280 + 217 s), the mean (± s.d.) half-time of clearance of the radiolabel from the NODS and corneal region of interest was 406 ± 214 s whereas the radiolabelled solution had a mean (± s.d.) ocular surface residence time of 2.9 ± 1.5 s. 5 Pupil diameter and intraocular pressure were measured for 5 h post-administration of the NODS and the solution. After both treatments pupil diameter was significantly constricted in the test eye when compared with the control eye (P < 0.001; Student's paired t-test). Pupil diameter was constricted by 52% after administration of the NODS and by 35% after administration of the solution. 6 Intraocular pressure was significantly reduced in the test eye compared with the control eye after administration of the NODS (P < 0.05) but not after administration of the solution. 7 There were no apparent differences in degree of pharmacological action of pilocarpine between subjects with longer half-times of NODS dissolution and those with shorter half-times, indicating that drug diffusion from the matrix was not rate-limiting for the magnitude of the pharmacological effect.
Centrally acting dopamine agonists (e.g. bromocriptine) and dopamine transport inhibitors (e.g. GBR12909) are known to inhibit oestradiol-induced prolactin release. The capacity of peripherally restricted compounds to do likewise, however, is unknown. Here, the effects of the peripherally restricted dopamine receptor agonist carmoxirole on oestradiol-induced prolactin release were investigated. Dual-cannulated ovariectomized rats were used, so that a robust, reproducible response to exogenous oestrogen could be induced and sequential blood samples were taken with minimal stress. Carmoxirole (15 mg/kg) inhibited oestradiol-induced prolactin release, similar to bromocriptine and GBR12909. However, carmoxirole also induced a rapid, transient, oestradiol-independent release of prolactin. These data show that peripherally restricted dopamine receptor agonists are sufficient to inhibit oestradiol-induced prolactin release. Like centrally acting compounds, they may therefore be expected to affect the incidence of prolactin-dependent tumours in rat carcinogenesis studies without inducing central-mediated side effects.Understanding the relevance or translation of pre-clinical drug effects to the clinic is critical for accurate human risk assessment for new pharmaceutical agents. In particular, accurate identification of specific mechanisms of serious toxicities observed in non-clinical species, and translation of specific mechanism in human beings can provide a scientific basis with which to evaluate specific risk in human beings. For example, it is known that some endocrine modulators can affect the incidence of particular tumours in life-time rat carcinogenicity bioassays, but not in human beings [1]. More specifically, the centrally active dopamine (D2) receptor agonist, bromocriptine, can induce hypoprolactinaemia in rats and human beings, but increases the incidence of hyperplastic proliferative endometrial lesions and benign and malignant uterine tumours only in rats [2], which has been postulated to be due to a lesser impact of prolactin on ovarian steroidogenesis in human beings [3].Prolactin is a peptide hormone spontaneously produced and secreted by lactotrophs in the anterior lobe of the pituitary gland under control by hypothalamic factors. In the rat, three dopaminergic systems [tuberoinfundibular (TIDA), tuberohypophyseal and periventricular hypophyseal dopaminergic neurons] regulate prolactin release, with the relative contribution varying between reproductive, physiological and pathological stages [4]. Hypothalamic dopaminergic neurons play a central role in the regulation of prolactin release by exerting an effect on the lactotrophs via the D2 receptor [5,6]. However, dopamine can also affect prolactin secretion by acting in the hypothalamus [7,8]. The pituitary lactotroph population is not entirely homogenous; mammosomatotropes, which are particularly common in neonatal rats, are differentiated into lactotrophs under the influence by oestrogens and secrete both prolactin and growth hormone [9]...
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