Musculoskeletal side effects are a widely reported consequence of administration of particular matrix metalloproteinase inhibitors (MMPi) in clinical trials. We describe here histopathological findings during dog studies with a fairly selective MMPi AZM551248, that are consistent with these human clinical changes. They were characterized by a dose-and time-dependent formative connective tissue alteration we have termed "fibrodysplasia." The most sensitive site was the subcuticular connective tissue, although musculoskeletal tissues were also extensively involved. In the subcutis, changes occurred initially around pre-existing blood vessels, but then more diffusely. There was proliferation of cells showing myofibroblast differentiation identified by elevated levels of alpha-smooth muscle actin, fibronectin, and transforming growth factor beta, and the deposition of collagen type III with a lesser quantity of collagen type I. On longer-term administration at lower doses, there was evidence of active fibrodysplasia arising and resolving during the dosing period, resulting in the multifocal deposition of mature collagen. Although there was organ specificity, essentially identical changes occurred at multiple connective tissue sites. We conclude that MMPi-induced fibrodysplasia in animals and, by inference, musculoskeletal side effects in humans are potentially diffuse connective tissue disorders.
(carboxymethyl)phenoxy]ethyl)-N -(β-hydroxyphenethyl)ammonium chloride], are β3-adrenoceptor stimulants with selectivity for brown adipose tissue. ZD7144 is the hydrochloride salt of the S-enantiomer of the racemic amide ZD2079. They were developed as potential novel treatments for obesity and non-insulin-dependent diabetes mellitus. Male and female rats were dosed separately by gavage for a minimum of 28 days with 0, 10, 50, and 500 mg/kg/day of ZD7114 or with 0, 10, 30, and 150 mg/kg/day of ZD2079. Two further groups of male and female rats were dosed with 0 and 500 mg/kg/day of ZD7114 for 28 days and were then allowed a 6-wk, undosed withdrawal period. At high doses, both compounds caused urinary tract toxicity, which primarily affected the distal tubules and collecting ducts of the kidney via tubular necrosis. They also caused ureteric inflammation, cystitis, and accumulation of crystalline inclusions throughout the urinary tract. As a result of urinary tract toxicity, affected animals from one or both studies showed reduced red blood cell indices, lower platelet counts, and higher white cell counts. Blood chemistry revealed lower plasma concentrations of glucose (7.28
AZD3783, a cationic amphiphilic drug and a potent inhibitor of the 5-hydroxytryptamine
(5-HT1B) receptor, was explored as a potential treatment for depression. To
support clinical trials, repeat dose toxicity studies in rats and dogs were conducted.
Here we report toxicity findings in dogs after dosing from 1 to 3 months. In the 1-month
study, there were minimal neuronal vacuolation in the brain, a marked increase in liver
enzymes accompanied by hepatocellular degeneration/necrosis and phospholipidosis (PLD),
and PLD/cholecystitis in the gallbladder of animals dosed at 47 mg/kg/day. In the 3-month
study, neurotoxicity resulted in euthanasia of one animal dosed at 30 mg/kg/day after 86
days. Extensive pathologic changes were seen in all animals in retina epithelium
(inclusion bodies), brain (neuronal vacuolation, degeneration, or necrosis and nerve fiber
degeneration), spinal ganglia (vacuolation, degeneration, or necrosis), as well as sciatic
and optic nerves (degeneration). Pigment-laden macrophages were observed in the lung,
kidney, liver, gallbladder, bone marrow, gastrointestinal tract, and lymphoid tissues.
Also seen were vitrel and retinal hemorrhage in the eyes. A brain concentration and
pathology study showed that the concentration of AZD3783 in the brain was approximately 4
times higher than in the plasma after 4 weeks of dosing, however, they were similar in all
regions examined, and did not correlate with areas with pathologic findings. Our findings
with AZD3783 in dogs have not been reported previously with other CNS compounds that
effect through serotonergic pharmacology.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.