Phospholipidosis in neurons caused by posaconazole, without evidence for functional neurologic effects.

The azole antifungal drug posaconazole caused phospholipidosis in neurons of the central nervous system, dorsal root ganglia of the spinal cord, and myenteric plexus in chronic toxicity studies in dogs. The time of onset, light and electron microscopic features, neurologic and electrophysiologic effects on the central and peripheral nervous systems, and potential for regression were investigated in a series of studies with a duration of up to one year. Nuclei of the medulla oblongata were the prominently affected areas of the brain. Neurons contained cytoplasmic vacuoles with concentrically whorled plasma membrane-like material (i.e., multilamellar bodies) morphologically identical to that commonly caused in other tissues by cationic amphiphilic drugs. Some axons in the brain and spinal cord were swollen and contained granular eosinophilic, electron-dense lysosomes. There were no features suggesting degeneration or necrosis of neurons or any associated elements of nervous tissue. The earliest and most consistent onset was in neurons of dorsal root ganglia. The observed neural phospholipidosis did not result in any alteration in the amplitude or latency of the auditory, visual, or somatosensory evoked potentials. The histopathologic changes did not progress or regress within the three-month postdose period. The results indicate that phospholipidosis can be induced in central and peripheral neurons of dogs by administration of posaconazole, but this change is not associated with functional effects in the systems evaluated.

Ziracin-induced congenital urogenital malformations in female rats.

Spontaneous hypospadias is seldom observed in rats in contrast to its occurrence in 1 out of 250 human births. Ziracin, an antibacterial of the everninomycin class under development for serious enterococcal, staphylococcal, and streptococcal infections, caused anomalies of the external genitalia in F1 female rats and decreased reproductive performance. To characterize the urogenital malformations and determine the period of sensitivity to the effects of Ziracin during development, pregnant rats (F0) were administered 60 mg/kg IV of Ziracin from GD6 to LD21, GD6 to 13, GD14 to the last day of gestation or LD0 to 21. Controls received saline or placebo from GD6 to LD21. Ziracin-induced changes occurred in F1 rats exposed from GD6 to LD21 and GD14 to the last day of gestation, indicating that the period of sensitivity to Ziracin was from GD 14 to the last day of gestation. The urogenital abnormalities consisted of cranial displacement of the urethral opening within the vagina from its normal location at the tip of the genital tubercle. When the urethrovaginal junction occurred at the distal third of the vagina, it created an urogenital cloaca. As a result, ascending infections were seen in the urinary and genital tract. No differences in survivability, body weight, and date of vaginal opening were observed in F1 females. The estrous cycles were slightly prolonged. The mating and fertility indices were decreased as a result of the urogenital anomalies. The mammary glands of pregnant F1 females were underdeveloped, thus F2 pups from affected F1 females had a decreased survival rate. Although the cause of these effects is not known, the findings are consistent with a potential hormonal mechanism.

Effects of perinatal loratadine exposure on male rat reproductive organ development.

Normal pre- and postnatal male reproductive development and function is dependent upon testicular androgen production and is sensitive to antiandrogenic perturbations. It was of interest to determine if the H(1) histamine antagonist loratadine had the potential to alter androgen-mediated reproductive development in the rat, a sensitive species for detecting antiandrogenic effects. Loratadine was administered orally by gavage to pregnant Sprague-Dawley rats at doses of 4, 12 or 24 mg/kg from gestation day 7 to postnatal day 4, encompassing the period of androgen-dependent male reproductive development. Vehicle control rats received 0.4% aqueous methylcellulose. Dams were allowed to deliver naturally and rear their offspring until postnatal day 21. On postnatal day 21 male offspring were retained for further evaluation of androgen-dependent endpoints and the female offspring were euthanized and their sex confirmed internally. Males were necropsied from postnatal day 72 to 85. Dams administered 24 mg/kg of loratadine exhibited a transient 45% decrement in maternal body weight gain at the initiation of dosing (gestation days 7-9). Mean pup body weight on postnatal days 1 and 4 were approximately 4% lower than controls. No other effects on offspring growth were observed. Anogenital distance on postnatal day 1 was unaffected by loratadine exposure. Loratadine exposure did not induce the retention of nipples in male rats, affect preputial separation, or induce external malformations, including hypospadias. Seminal vesicle and prostate weights were not decreased by loratadine exposure. These data clearly demonstrate that systemic loratadine exposure, in multiples up to 26 times clinical exposure levels, does not exhibit in vivo antiandrogen activity, as evidenced by the absence of alterations or malformations in androgen-dependent reproductive tissues in male rats exposed to loratadine during the critical period of androgen-dependent development.

Porcine toxicology studies of SCH 58500, an adenoviral vector for the p53 gene.

Adenoviral vectors are being actively investigated for their potential utility in gene therapy. SCH 58500, a replication-deficient adenoviral vector, carries the normal p53 tumor suppressor gene, which is frequently mutated or absent in several human cancers. To assess the potential toxicity associated with adenoviral use, Yorkshire pigs were dosed by intravenous, intrahepatic, or local routes (subcutaneous and intradermal) to support a variety of potential clinical indications. Porcine cells were shown to support replication of wild-type human adenovirus. The nonlethal and asymptomatic dose in pigs following dosing via the intrahepatic route was greater than 3 x 10(8) plaque-forming units (pfu)/kg (2.2 x 10(11) particles/kg), but less than 2.1 x 10(9) pfu/kg (1.5 x 10(12) particles/kg). By the intravenous route it was 1 x 10(8) pfu/kg, and by the ip route it was greater than or equal to 3 x 10(8) pfu/kg. In a multicycle intraperitoneal study in pigs, the high dose of 3 x 10(8) pfu/kg caused an increased antibody and/or an inflammatory response. By the intravenous route, plaque-forming units were present in most pigs at 5 min postdose, but only in a few at 10 min postdose. No expression was found in gonadal tissue approximately 3 weeks after a single intravenous injection of 3 x 10(8) pfu/kg. At high intrahepatic doses (about 1.5 x 10(12) particles/kg), acute cardiovascular and hemodynamic effects were found, which in subsequent studies were also present at high doses by intravenous administration. Based on these findings, careful evaluation of hemodynamic parameters in patients receiving systemic doses of SCH 58500 is warranted.

Rodent nonclinical safety evaluation studies of SCH 58500, an adenoviral vector for the p53 gene.

SCH 58500 is a replication-defective recombinant adenoviral vector containing the cloned human wild-type (normal) tumor suppressor gene p53. SCH 58500 is in trials to evaluate potential clinical utility. A series of toxicology studies in rats and mice were conducted via multiple routes of exposure to support these programs. The nonlethal and asymptomatic dose in rats following a 14-day observation period was equal to 7.5 x 10(7) plaque-forming units (pfu)/kg (5.6 x 10(10) particles/kg) by intravenous or intraperitoneal route and was similar by the ip route, following 4 weeks of dosing. The high dose of 1.5 x 10(9) pfu/kg (1.1 x 10(12) particles/kg) was lethal by the i.v. route and inflammatory to the peritoneal cavity by the ip route. SCH 58500 was rapidly cleared from the systemic circulation in rats (serum t(1/2) of 7 to 9 min) following iv administration. Administration by other routes resulted in no (sc) or delayed (ip) serum levels. Since most rats in the i.v. rat study died within 24 h postdose, another study to evaluate potential mechanisms of toxicity in rats was designed in which rats were killed at intervals following a single i.v. dosing. A single high i.v. dose of SCH 58500 (1.1 x 10(12) pfu/kg) was associated with lethargy, soft feces, a ruffled-hair coat, and death within 1 h postdose. Potential mechanisms of toxicity appeared to include a mild coagulopathy and/or vasculopathy, resulting in consumption of platelets and clotting factors, leakage or loss of intravascular fluid, hemoconcentration, electrolyte and/or fluid shifts, a moderate stress and/or inflammatory response, and a mild, direct or indirect toxic effect on liver and/or kidney tissue. These findings suggest a multifocal cause for acute lethality following i.v. dosing in rats.