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  • 1
    Electronic Resource
    Electronic Resource
    Lipidosis-like alterations in spinal cord and cerebellar cortex of rats treated with chlorphentermine or tricylic antidepressants (1974)
    Springer
    Acta neuropathologica 29 (1974), S. 237-249 
    Details
    ISSN: 1432-0533
    Keywords: Chlorphentermine ; Iprindole ; 1-Chloro-amitriptyline ; Central Nervous System ; Lipidosis, Drug-Induced
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Prolonged treatment of rats with the anorectic drug chlorphentermine or the tricyclic antidepressants iprindole and 1-chloro-amitriptyline caused the formation of numerous cytoplasmic inclusions in nerve cells of the cervical spinal cord and cerebellar cortex. The antidepressant drugs clomipramine, amitriptyline and noxiptiline had only weak or no effects. The abnormal, membrane-bound inclusions consisted either of parallel or concentrically arranged lamellae, or they exhibited crystalloid or reticular internal patterns. The alterations correspond to previous observations on extraneural tissues of drug-treated animals. According to a proposed concept, the present findings are interpreted to reflect a drug-induced lipidosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685259
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  • 2
    Electronic Resource
    Electronic Resource
    Retinal lipidosis in albino rats treated with chlorphentermine and with tricyclic antidepressants (1976)
    Springer
    Acta neuropathologica 35 (1976), S. 55-67 
    Details
    ISSN: 1432-0533
    Keywords: Pigment epithelium ; Albino rat ; Neuroretina ; Phospholipid storage ; Chlorphentermine ; Tricyclic antidepressants
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Retinal pigment epithelium is known to be engaged in continuous phagocytosis and digestion of old discs of visual cell outer segments, which have a high phospholipid content. The present ultrastructural study was focused mainly on the effects, upon pigment epithelium, of several drugs that are thought to interfere with the enzymatic degradation of phospholipids. Albino rats received high oral doses of chlorphentermine, iprindole, l-chloroamitriptyline, imipramine, or clomipramine. After treatment for several weeks the pigment epithelial cells were doubled in height due to deposition of excessive amounts of abnormal cytoplasmic inclusions which had a crystalloid substructure. Such inclusions which are known from previous studies to be associated with drug-induced phospholipid storage are suggested to contain non-digestible phospholipids, which in pigment epithelium originate mainly from phagocytosed outer segment discs. The alterations were reversible by withdrawal of the drugs. The functional implications of the epithelial alterations remain to be elucidated. Additional examination of the neuroretina revealed numerous abnormal inclusions, mainly of multilamellated structure. Ganglion cells were affected most. The neuroretinal alterations were reminiscent of those described in human cases of inherited lipidoses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00688943
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  • 3
    Electronic Resource
    Electronic Resource
    Effects of several lipidosis-inducing drugs upon the area postrema and adjacent medullary nuclei of adult rats (1980)
    Springer
    Acta neuropathologica 52 (1980), S. 179-187 
    Details
    ISSN: 1432-0533
    Keywords: Medulla oblongata ; Rat ; Chlorophentermine ; Chloroquine ; Lipidosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The present study is concerned with the question of whether or not amphiphilic drugs (chloroquine, quinacrine, perhexiline) that fail to induce general lipidosis in the central nervous system (CNS) of adult rats can produce lipidosis in a circumventricular organ (area postrema) not furnished with a blood-brain barrier. Chlorphentermine known to induce general lipidosis in CNS of adult rats served as reference compound. All drugs, when chronically applied in high oral doses, induced significant perikaryal lipidosis in the area postrema. In the adjacent nuclei (nucleus tractus solitarii, nucleus dorsalis nervi vagi, nucleus nervi hypoglossi, nucleus gracilis), only chlorphentermine caused generalized lipidosis, whereas the other drugs had either limited or no effects. The present findings strongly suggest that the exemption, of most regions of the CNS of adult rats, from lipidosis induced by chloroquine and others is due to hindered drug distribution across the blood-brain barrier, rather than being due to non-susceptibility of central neurons toward the lipidosis-inducing action of the drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00705806
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  • 4
    Electronic Resource
    Electronic Resource
    Effects of several lipidosis-inducing drugs upon the area postrema and adjacent medullary nuclei of adult rats (1981)
    Springer
    Acta neuropathologica 53 (1981), S. 41-50 
    Details
    ISSN: 1432-0533
    Keywords: Giant axon swellings ; Rat ; Drug-induced lipidosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This study is concerned with the structure and topographic distribution of axonal alterations in the area postrema and in several adjacent nuclei of adult rats treated with different lipidosis-inducing drugs. The effects of three compounds (chloroquine, quinacrine, perhexiline) that seem to be largely excluded from most parts of the brain except circumventricular organs were compared with a reference compound (chlorphentermine) that has general access to the brain of adult rats. Only chlorphentermine caused generalized axonal alterations (intra-axonal accumulation of polymorphous osmiophilic materials, giant axonal swellings) in all inspected nuclei (area postrema, nucleus gracilis, nucleus tractus solitarii, nucleus nervi hypoglossi, nucleus dorsalis nervi vagi), with nucleus gracilis possessing the most vulnerable axons and axon terminals. The axonal effects of chloroquine were severe only in area postrema and in the closely adjacent neuropil of nucleus gracilis and nucleus tractus solitarii, whereas in the remaining regions axonal alterations were either moderate (lateral portions of nucleus gracilis) or absent. Axonal effects of quinacrine and perhexiline were confined to area postrema. The findings suggest that the topography of the severe axon alterations is greatly dependent on drug distribution. It is concluded that two factors have generally to be considered as responsible for the giant axon swellings found after application of lipidosis-inducing drugs: (a) local drug action upon the axon itself, and (b) lysosomal overloading in the corresponding perikaryon, with factor (a) probably being more potent than factor (b).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00697183
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  • 5
    Electronic Resource
    Electronic Resource
    Perhexiline induces generalized lipidosis in rats (1978)
    Springer
    Journal of molecular medicine 56 (1978), S. 309-310 
    Details
    ISSN: 1432-1440
    Keywords: Perhexilin-Maleat ; generalisierte Lipidose ; Ratte ; Perhexiline maleate ; Generalized lipidosis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Administration of perhexiline (Pexide®) to rats causes generalized occurrence of lamellated and crystalloid cytoplasmic inclusions which resemble those described in patients with perhexiline-induced polyneuropathy. It is concluded that perhexiline being an amphiphilic cationic compound is a potent inducer of generalized lipidosis.
    Notes: Zusammenfassung Perhexilin (Pexid®) verursacht bei der Ratte das generalisierte Auftreten von lamellären und kristalloiden zytoplasmatischen Einschlußkörpern, die denjenigen gleichen, die bei Patienten mit Perhexilin-induzierter Polyneuropathie beschrieben worden sind. Aus den vorgelegten Befunden wird geschlossen, daß Perhexilin, eine amphiphile kationische Verbindung, ein starker Induktor einer generalisierten Lipidose ist.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01489178
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  • 6
    Electronic Resource
    Electronic Resource
    Lipidosis-like alterations in cultured macrophages exposed to local anaesthetics (1984)
    Springer
    Archives of toxicology 55 (1984), S. 229-232 
    Details
    ISSN: 1432-0738
    Keywords: Local anaesthetics ; Drug-induced lipidosis ; Cationic amphiphilic drugs ; Structure-response relationship ; Cell culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In this ultrastructural study, the simple model of cultured rat peritoneal macrophages was used to examine whether local anaesthetics can induce lipidosis-like alterations. Exposure (24 h) of macrophages to 1×10−5 M dibucaine, or to 5×10−5 M tetracaine, quinidine, and quinine, respectively, led to the occurrence of lamellated cytoplasmic inclusions in most cells. This is interpreted as indicating lipidosis. Type and degree of alterations were similar to those induced by the reference compound chlorphentermine (5×10−5 M) for which lipidosis has previously been shown by biochemical methods. Tocainide (5×10−5 M) caused weak alterations only; procaine (5×10−5 M) was without effect. The differential potencies presently observed are paralleled by differential affinities of the local anaesthetics towards polar lipids as determined by other authors. The present results support the hypothesis that the lipidosis-inducing potency inherent to an amphiphilic cationic drug can be tentatively predicted on the basis of its affinity to polar lipids, although it may be obscured by secondary factors when the drug is administered to intact organisms. The present communication emphasizes the advantage of cell cultures over animal experiments (a) for studying the structure-response relationships underlying drug-induced lipidosis, and (b) to reliably ascertain that a given drug has only low lipidosis-inducing potency or none at all as found for tocainide and procaine, respectively.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00341016
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  • 7
    Electronic Resource
    Electronic Resource
    Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice (2000)
    [s.l.] : Macmillian Magazines Ltd.
    Nature 406 (2000), S. 902-906 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Lysosome-associated membrane protein-2 (LAMP-2) is a highly glycosylated protein and an important constituent of the lysosomal membrane. Here we show that LAMP-2 deficiency in mice increases mortality between 20 and 40 days of age. The surviving mice are fertile and have an almost normal ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/35022595
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  • 8
    Electronic Resource
    Electronic Resource
    Keratopathy in rats after treatment with tilorone (1986)
    Springer
    Graefe's archive for clinical and experimental ophthalmology 224 (1986), S. 377-383 
    Details
    ISSN: 1435-702X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract According to clinical reports, the antitumor drug tilorone induces corneal opacities in patients. The present communication shows that keratopathy can be experimentally reproduced in rats and describes the cellular alterations underlying the corneal opacities. Tilorone was applied either orally (60–90 mg/kg) for several weeks or topically (2%) for a few days. Biomicroscopic examination performed after treatment for 6 weeks or longer revealed fine punctate opacities throughout the corneal stroma. Ultra-structurally, the keratocytes were swollen due to large, optically empty vacuoles in the cytoplasm. Similar, albeit smaller, vacuoles were also numerous in the endothelium and less frequent in the epithelium. Histochemical experiments showed that the cellular alterations represented lysosomal storage of polyanionic substances, most probably sulfated glycosaminoglycans, thus mimicking the cytological picture of mucopolysaccharidosis. Upon discontinuation of drug treatment, the alterations tended not to recede. This keratopathy in rats is part of a generalized mucopoly-saccharidosis-like disorder induced by tilorone.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02150034
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  • 9
    Electronic Resource
    Electronic Resource
    Cultured corneal fibroblasts as a model system for the demonstration of drug-induced mucopolysaccharidosis (1990)
    Springer
    Archives of toxicology 64 (1990), S. 291-298 
    Details
    ISSN: 1432-0738
    Keywords: Mucopolysaccharidosis, drug-induced ; Tilorone ; Lysosomes ; glycosaminoglycans ; Cell culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The purpose of the present investigation was to establish a cell culture system suitable for demonstrating the drug-induced lysosomal storage of sulfated glycosaminoglycans (GAGs). This is a drug side-effect which was previously studied in animals treated with the di-cationic amphiphilic compound tilorone and congeners, and which is likely to occur in humans, too. Cultured corneal fibroblasts of rats were exposed to tilorone for 72 h. They developed histochemical and cytochemical alterations indicative of mucopolysaccharidosis and resembling those occurring in vivo. The threshold drug concentration was found to be below 0.7 μM. The reversibility of the lysosomal GAG storage was low. An increase in the drug concentration to 10 μM produced additional unspecific lysosomal alterations, while the mucopolysaccharidosis-like lesions became less prominent. Concentrations of 40 μM and 80 μM caused unspecific cytoplasmic vacuolation and cell death, respectively. The present model system appears suitable for screening investigations of newly developed drugs with respect to their mucopolysaccharidosis-inducing potential and for investigating the structure-activity relationships underlying this adverse drug effect. Care should be taken not to use too high drug concentrations which cause unspecific lysosomal lesions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01972989
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  • 10
    Electronic Resource
    Electronic Resource
    Histochemical evidence for lysosomal storage of acid glycosaminoglycans in splenic cells of rats treated with tilorone (1982)
    Springer
    Histochemistry and cell biology 76 (1982), S. 71-87 
    Details
    ISSN: 1432-119X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Tilorone, an agent with antiviral and antitumor activities, has previously been reported to produce clear cytoplasmic vacuoles in many cell types of the rat. The present study on rat spleen was planned to investigate the ultrastructural and histochemical features of the tilorone-induced vacuoles occurring in sinus endothelium, trabecular smooth muscle cells, and macrophages of the red pulp. Evidence was obtained that the vacuoles represent lysosomes overloaded with acid glycosaminoglycans (aGAG). The main purpose of the present study was to overcome the technical difficulties of preserving the intralysosomal storage materials which were highly water-soluble and non-fixable by aldehyde fixatives. Preservation, at least for the light microscopical level, was achieved by freeze drying and by means of cationic dyes which served also to characterize the storage materials on the basis of their acidities. Tissue slices were used to determine the critical MgCl2 concentration necessary to abolish Alcian blue staining; cartilage and mast cells served as references. For the storage material in sinus endothelium, the critical MgCl2 concentration was found to be 〉0.7 M, as compared to 〉0.5 M for cartilage and 〉0.9 M for mast cells. The storage materials in trabecular cells and macrophages were slightly less acidic than cartilagineous matrix and more heterogeneous than that in sinus endothelium. Ultrastructurally, positive staining with high iron diamine (HID) confirmed the presence of aGAG within the tilorone-induced vacuoles.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00493287
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