Hyperpigmentation of the skin associated with minocycline therapy.

Skin biopsy specimens and discolored fingernails from minocycline-treated patients were examined by light and electron microscopy, histochemistry, and energy-dispersive x-ray analysis. Both hyperpigmented and adjacent normally pigmented skin samples contained pigment-laden macrophages in the dermis, although these cells were more numerous in the hyperpigmented skin samples. Elemental analysis showed that both pigment deposits and stratum corneum of hyperpigmented skin samples contained iron and calcium. Discolored areas of fingernails from a minocycline-treated patient also contained iron and calcium. Both skin and nail discoloration were possibly due to the presence of an iron chelate of minocycline and/or quinoid derivatives of minocycline. The presence of iron-containing pigment in normal as well as hyperpigmented skin may have predisposed to formation of minocycline-associated pigment in these patients.

Thyroid gland pigmentation and minocycline therapy.

Thyroid pigments in black thyroid glands from minocycline-treated patients were compared by light and electron microscopy, histochemistry, and energy-dispersive x-ray analysis with minocycline-induced pigment in thyroid glands of laboratory animals, and with naturally occurring lipofuscins in untreated laboratory animals and humans. All thyroid samples examined contained nonbirefringent, Schmorl-positive pigment. However, the pigments in black thyroids from minocycline-treated patients resembled lipofuscins of untreated humans since both fluoresced and were Ziehl-Neelsen- and Sudan IV-positive. Minocycline induced pigment in rats was nonfluorescent and Ziehl-Neelsen- and Sudan IV-negative. Ultrastructurally, pigments in black thyroid glands of minocycline-treated humans resembled lipofuscins in untreated humans, and initial elemental analyses yielded similar spectra. Repeated analyses of the most electron-dense pigment deposits yielded spectra that resembled those of minocycline-induced pigment in laboratory animals-ie, both contained calcium. Black thyroid glands associated with minocycline administration contained predominantly lipofuscins with a small amount of another, possibly minocycline-related pigment. The absence of functional changes in patients and animals given minocycline suggests that discoloration of the thyroid gland associated with minocycline administration is innocuous. This is further supported by the lack of documented changes in thyroid physiology in patients that have received tetracyclines for a variety of indications in the last 30-odd years since their introduction to therapy.

The LEDTOX Necropsy System: an interactive protocol driven gross postmortem examination data collection system.

The LEDTOX Necropsy System consists of a series of programs which provide for the real time collection of gross postmortem data while interacting with the LEDTOX Protocol, Animal Weighing/Clinical Observation, Palpable Mass, Clinical Pathology, Histopathology and Animal Colony Management Systems. Special procedures and lists of tissues specified in the protocol for various necropsy activities drive to data collection routines. Key system features include: system generated gross findings menu to facilitate data entry; designation of key phrases to be used for data summarization; online confirmation of palpable masses identified during life; online review of clinical observation and clinical pathology data. Outputs include: incidence summary of gross postmortem findings; tissue examination/sampling summary; correlation of antemortem and postmortem mass/neoplasm data; organ weight statistical summary. With completion of this module, 90-100% of the routine tables for postmortem reports are immediately available to pathologists for data interpretation.

Safety assessment of new anticancer compound, mitoxantrone, in beagle dogs: comparison with doxorubicin. II. Histologic and ultrastructural pathology.

Beagle dogs received either doxorubicin hydrochloride (1.75 mg/kg) or mitoxantrone (0.125 or 0.25 mg/kg) iv once every 3 weeks. These doses were equivalent to 36.05 mg/m2 of doxorubicin and 2.58 or 5.15 mg/m2 of mitoxantrone. Sequential endomyocardial biopsies were performed approximately 2 weeks after the fourth (or fifth), seventh, and ninth doses in order to monitor histopathologic and ultrastructural changes during the study. Myocardial lesions that progressed with time and dose were observed in heart samples from dogs that received doxorubicin, but not in dogs that received mitoxantrone. The myocardial lesions induced by doxorubicin were observed with cumulative doses as low as 144 mg/m2. Myocardial changes, which did not progress with time and cumulative dose, were observed in dogs that received either dose of mitoxantrone. The earliest observable evidence of doxorubicin-associated cardiotoxicity was seen morphologically in biopsy material before clinical signs of cardiotoxicity. No evidence of cardiotoxicity, either morphologic or clinical, was seen in dogs treated with the maximum tolerated dose of mitoxantrone during the course of treatment. The dog appears to be a suitable model for studying the chronic cardiotoxic effects of anthracyclines and for monitoring effects of compounds such as mitoxantrone, which show a spectrum of activity and mechanism of action similar to that of anthracycline compounds.

Chemically Induced Hepatocellular Proliferative Changes in the Rat Without Evidence of Neoplastic Transformation.

The hypothesis that hepatocellular proliferative changes give rise to autonomous, neoplastic lesions in rodents was tested in this study in which hepatoproliferative lesions induced in rats by feeding an experimental psychoactive drug, cyproximide, were examined at various times during the course of a 24 month study. A total of 610 male and female rats (Charles River Laboratories COBS®CD®(SD)BR, Wilmington, Mass.) were distributed into three groups. Each of two treatment groups contained 230 rats given 0.1% or 0.4% of cyproximide in the diet. One hundred and fifty rats were given a drug-free diet and served as controls. Five males and five females from each group were sacrificed for postmortem examination after 6, 12 and 20 months of drug diet feeding after which remaining rats were retained for recovery (nontreatment) periods of 18, 12 and 4 months, respectively. An additional 25 males and 25 females from each dose level were treated for 24 months and then sacrificed along with all surviving recovery and control rats. The results of this study demonstrated that the incidence of proliferative lesions was greater in the liver of treated rats (especially females) than in control rats; however, the incidence of hepatocellular neoplasms was the same in treated and control rats.