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Biomedical subjects

R Lüllmann-Rauch

Publications and source records attributed to R Lüllmann-Rauch.

At least 55 records · Page 3Linked to original sources
PubMed1990

Mucopolysaccharidosis (MPS) in ocular tissues as induced by amphiphilic di-cationic drugs.

The immunostimulatory drug tilorone (2,7-bis(2- (diethylamino)ethoxy)-9H-fluorene-9-one) has previously been described to induce keratopathy in patients and in rats; in the latter, lysosomal storage of sulfated glycosaminoglycans (mucopolysaccharidosis, MPS) was found to be the reason for corneal clouding. In the present histochemical and ultrastructural study, several ocular tissues of rats were examined after chronic treatment with tilorone and two other immunostimulatory agents (3,6-bis(2-(dipiperidyl)ethoxy)-acridine and the diethylamino analogue). The acridine derivatives hardly affected the cornea and sclera. Tilorone as well as the acridine derivatives induced significant MPS in ciliary body, iris, and choroid. While the functional consequences of drug-induced MPS in ocular tissues are not known yet, except for the cornea, this adverse drug action should be taken into account when new compounds are designed that share certain physicochemical features with tilorone. One molecular feature essential for the MPS-inducing potency of a drug appears to be the dicationic amphiphilic character.

Acridines↗
PubMed1989

Mucopolysaccharidosis and lipidosis in rats treated with tilorone analogues.

The experimental immunomodulatory agent tilorone was previously reported to induce generalized mucopolysaccharidosis (lysosomal storage of sulfated glycosaminoglycans) and lipidosis in rats. While lipidosis is a side effect common to many cationic amphiphilic compounds, none of them except tilorone has been known to cause mucopolysaccharidosis in intact animals. The purpose of the present histochemical and ultrastructural study was to examine whether or not mucopolysaccharidosis can be induced by tilorone analogues. Three analogues were selected and administered to rats in short-term and subchronic experiments, and liver, spleen, kidney, and cornea were examined. The analogues caused generalized cellular lesions which had the same histochemical and cytological characteristics and the same distribution as the lesions produced by tilorone. The results show that the ability to induce mucopolysaccharidosis is not a unique property of tilorone; this drug side effect should be taken into account when developing new drugs with molecular structures resembling that of tilorone.

Animals↗
PubMed1989

Experimental mucopolysaccharidosis: preservation and ultrastructural visualization of intralysosomal glycosaminoglycans by use of the cationic dyes cuprolinic blue and toluidine blue.

The cationic dyes Cuprolinic Blue (CB) and Toluidine Blue (TB) were used to preserve the intralysosomal storage material accumulating in tilorone-induced mucopolysaccharidosis. As shown in previous studies, the stored glycosaminoglycans (GAGs) are leached during the conventional fixation procedure, with the result that the lysosomes appear empty. In the present study, the liver, spleen, and cornea-conjunctiva of tilorone-treated rats were examined. The application of CB in the presence of 0.1 M or 0.3 M MgCl2 simultaneously with, or subsequently to the primary fixative yielded electron-dense precipitates within the storage lysosomes. When TB (0.1%) was added to the primary fixative, the storage lysosomes contained filamentous structures arranged in reticular patterns. With increasing TB concentrations (up to 1%) the lysosomes increasingly often showed apparently amorphous storage material which was continuous with the reticular filamentous structures. Similar ultrastructural patterns were obtained with GAG-TB complexes prepared in vitro. The intralysosomal storage material preserved by TB is interpreted as GAG-TB precipitates. In conclusion, the use of CB provides a method which allows direct cytochemical demonstration of the subcellular sites of GAG-storage. The use of TB represents an easy method to obtain electron micrographs pathognomonic of the mucopolysaccharidosis induced by tilorone and congeners. Either method may be helpful to detect this adverse drug effect at the subcellular level.

Animals↗
PubMed1988

On the alcianophilia of the drug suramin used as a tool for inducing experimental mucopolysaccharidosis.

The trypanocidal drug suramin was previously reported to induce mucopolysaccharidosis in rats; apart from the biochemical demonstration of increased tissue concentrations of sulfated glycosaminoglycans (GAGs), a strongly positive staining reaction with the cationic dye Alcian Blue was taken as indicating GAG-storage (Constantopoulos et al. 1983). The purpose of the present report is to point out a methodical pitfall. In model experiments it was found that suramin itself, being a polysulfated compound, gives a strongly positive reaction with Alcian Blue at pH 1. It is known that suramin is accumulated in the lysosomes and that high drug concentrations are retained in the tissues for weeks. Therefore a positive staining reaction with Alcian Blue observed in a given cell cannot be conclusively attributed to the storage of sulfated GAGs as has been done in the past. The present report may be a warning that, in the case of the suramin-induced animal model of mucopolysaccharidosis, the usual histochemical strategy, i.e. staining with cationic dyes, is not suitable for analysing the cellular distribution pattern of GAG-storage, since the inducing drug by itself reacts with the indicator dye.

Alcian Blue↗
PubMed1988

Mucopolysaccharidosis-like cellular alterations in chondrocytes of rats treated with tilorone.

The dicationic amphiphilic compound tilorone was previously shown to interfere with the lysosomal degradation of sulfated glycosaminoglycans (GAGs) of cultured cells and to cause mucopolysaccharidosis-like alterations in several organs of rats. Since chondrocytes belong to those cells that are severely affected in cases of inherited mucopolysaccharidoses, we wished to know whether this also holds true of the experimentally induced mucopolysaccharidosis. Young rats were treated with tilorone (50-80 mg/kg of body weight) for 2-17 weeks; chondrocytes in tracheal and costal cartilage and in the epiphyseal growth plates of the tibia and ribs were examined by electron microscopy and cytochemistry (acid trimetaphosphatase and staining with Cuprolinic Blue). The tracheal and costal chondrocytes showed numerous abnormal clear vacuoles. Some of them could be identified cytochemically as lysosomes filled with polyanionic storage material, probably sulfated GAGs. In the epiphyseal plate, only the resting chondrocytes were markedly affected, whereas those of the remaining zones were hardly altered; this may be due to the short life span of these chondrocytes in rat growth plates. The present results show that chondrocytes participate in the experimental mucopolysaccharidosis and suggest that, under normal conditions, the lysosomes of chondrocytes have to cope with a considerable load of GAGs.

Animals↗
PubMed1987

Fusion of storage lysosomes in experimental lipidosis and glycogenosis.

This ultrastructural investigation on renal collecting duct cells and hepatocytes of rats deals with the question of whether or not lipid-storage lysosomes as induced by cationic amphiphilic compounds retain their ability to fuse with autophagosomes/autolysosomes. These were recognized by their glycogen content which was made to persist by means of acarbose, an inhibitor of lysosomal alpha-glucosidase. To induce lipidosis, rats were pretreated for several weeks with chloroquine or chlorphentermine; they then received combined treatment with the lipidosis-inducing drug plus acarbose. In renal collecting duct cells, mixed storage lysosomes displaying the features of both lipidosis and glycogenosis were found to predominate, indicating that fusion between lipid-laden lysosomes and glycogen-containing autophagosomes/autolysosomes was efficient. Hepatocytes also displayed some mixed storage lysosomes; these were, however, regularly accompanied, within a given hepatocyte, by greater numbers of pure lipidosis-related inclusions and pure glycogen vacuoles. This observation indicates that in hepatocytes lipid-storage lysosomes were rather reluctant to fuse, thus displaying a feature of telolysosomes which are no longer capable of participating in cellular digestion.

Acarbose↗
PubMed1987

Amantadine-induced lipidosis. A cytological and physicochemical study.

The purpose of this study was to test whether or not the antiviral drug amantadine induces the structural features of lipidosis in intact animals (rats) and cultured cells, and to investigate the interactions between amantadine and phospholipids. Chlorphentermine was used as reference compound. When subchronically fed to rats at a daily dosage of approximately 180 mg/kg, amantadine induced ultrastructural symptoms of generalized lipidosis, the degree of which was, however, by far less marked than that previously reported for chlorphentermine. This was paralleled by the findings on cell cultures (rat peritoneal macrophages), where the lipidosis-inducing potency of amantadine was approximately 10-fold lower than that of chlorphentermine. As to drug-phospholipid interactions, amantadine had less marked effects than chlorphentermine upon the phase transition characteristics of phosphatidylcholine and phosphatidic acid; furthermore, amantadine was approximately 10-fold less potent than chlorphentermine in displacing Ca from phosphatidylserine monolayers. The present study has revealed a parallel between the comparatively low lipidosis-inducing efficacy inherent to amantadine and the comparatively low tendency to interact with phospholipids. It is suggested that the cage-like structure of the amantadine molecule hinders an effective intercalation of the drug into phospholipid aggregates, and that this is an essential factor responsible for the low inherent efficacy of amantadine with respect to lipidosis induction.

Amantadine↗
PubMed1986

Keratopathy in rats after treatment with tilorone.

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. Ultrastructurally, 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 mucopolysaccharidosis-like disorder induced by tilorone.

Animals↗
PubMed1985

Mucopolysaccharidosis-like alterations in cardiac valves of rats treated with tilorone.

The purpose of this study was to examine whether the aortic and mitral valves of rats are involved in the mucopolysaccharidosis-like disorder induced by tilorone. Rats were treated with large doses of the drug for periods of 1-21 weeks. After chronic drug treatment the leaflets of both heart valves were thickened and opaque. In all treated animals the spongiosa layer of the stroma was crowded with vacuolated cells; the fibrosa layer was altered only after prolonged treatment. Ultrastructurally, the vacuolated cells of the spongiosa could be identified as histiocytes and fibroblasts, the former being the most susceptible cell type. The fibroblasts of the fibrosa represented the least sensitive cell type. The histochemical results showed that the clear cytoplasmic vacuoles in the spongiosa cells were due to lysosomal storage of polyanionic material with staining characteristics similar to cartilage matrix. After discontinuation of drug treatment the alterations persisted for several weeks. The present study shows that heart valves are involved in the mucopolysaccharidosis-like disorder induced by tilorone. The molecular pathomechanism of the disorder and the exact identification of the storage material must await further analysis.

Animals↗
PubMed1984

Lipidosis-like alterations in cultured macrophages exposed to local anaesthetics.

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 (24h) of macrophages to 1 X 10(-5) M dibucaine, or to 5 X 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 X 10(-5) M) for which lipidosis has previously been shown by biochemical methods. Tocainide (5 X 10(-5) M) caused weak alterations only; procaine (5 X 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 for studying the structure-response relationships underlying drug-induced lipidosis, and to reliably ascertain that a given drug has only low lipidosis-inducing potency or none at all as found for tocainide and procaine, respectively.

Anesthetics, Local↗
PubMed1983

Tilorone-induced lysosomal storage mimicking the features of mucopolysaccharidosis and of lipidosis in rat liver.

This ultrastructural and histochemical study deals with the lysosomal storage phenomena occurring in the rat liver after repeated oral administration of tilorone, an agent with anti-tumor and anti-viral activities. In the sinusoidal endothelium and in Kupffer cells, the lysosomes were changed into large vacuoles which contained material with the histochemical characteristics of acid glycosaminoglycans. The alterations closely resembled those previously observed in the splenic red pulp of tilorone-treated rats. In hepatocytes, the lysosomes were converted into large multilamellated inclusions indicating storage of polar lipids. The results show that, in the rat liver, tilorone induces cellular alterations mimicking those of inherited mucopolysaccharidoses and lipidoses. After discontinuing drug treatment the two storage phenomena gradually faded at different rates: The lipidosis disappeared within 2 to 4 weeks, whilst mucopolysaccharidosis-like changes were still found 15 weeks after drug withdrawal. The occurrence of lipidosis is not surprising, since by its molecular structure tilorone can be regarded as belonging to the group of amphiphilic cationic drugs which often have this side effect. Much more surprising is the occurrence of mucopolysaccharidosis-like alterations. The exact biochemical identification of the polyanionic storage material and the molecular mechanisms responsible for this drug side effect remain to be established.

Animals↗
PubMed1983

Renal lysosomal protein digestion in experimental lipidosis.

The present study was undertaken to clarify whether or not chlorphentermine-induced lipidosis in the proximal tubules of the rat kidney interferes with lysosomal degradation of an absorbed exogenous protein. 125I-lysozyme was injected in vivo; its degradation was measured in vitro using slices from renal cortex. The subcellular distribution of the protein was examined by electron microscope autoradiography. Lysosomes structurally altered by the lipidosis were able to accumulate the protein, although to a smaller extent than normal-appearing lysosomes present in the same cells; the label persisted longer in the altered than in the normal-appearing lysosomes. Protein degradation was significantly decreased in renal cortical slices from chlorphentermine-treated rats compared with controls. The results indicate that experimentally-induced lipidosis is associated with decreased proteolytic efficiency of the lysosomes in proximal tubules.

Animals↗
PubMed1983

Citalopram-induced generalized lipidosis in rats.

This study was focussed on the question of whether or not the potential antidepressant citalopram, which is an amphiphilic cationic compound, can induce generalized lipidosis in animals. In a short term experiment, female rats were treated with a single oral dose (100 mg/kg) and the lymph node was examined by electron microscopy; a significant number of lymphocytes showed lamellated inclusions indicating lipidosis. In a subchronic experiment (7 weeks) female rats received 140 mg/kg per day, and several organs were examined. Marked lipidosis-like alterations were found in lymph node, adrenal cortex and medulla, kidney, lung and in a sympathetic ganglion. Mild lysosomal alterations were found in hepatocytes and retinal pigment epithelium. Lipidosis was very weak, or absent, in retinal ganglion cells, trigeminal ganglion cells and in hypothalamic neurosecretory perikarya. In addition, citalopram produced myopathic alterations in soleus muscle resembling those previously induced with other cationic amphiphilic drugs. Myopathy persisted during a drug-free recovery period of 4 weeks, whereas generalized lipidosis was reversible within 2-4 weeks. The present results support a previously proposed concept concerning the structure-response relationships underlying drug-induced lipidosis.

Animals↗
PubMed1983

Ultrastructural alterations in peripheral nerve trunks of rats subchronically treated with chlorphentermine or perhexiline.

The present study deals with the effects of two lipidosis-inducing drugs (chlorphentermine and perhexiline) upon the ultrastructure of large nerve trunks (sciatic and plantar nerves) of adult rats. Subchronic oral administration of high doses of either drug led to comparatively mild lipidosis-like alterations in Schwann cells and in other cell types of both nerve trunks. In addition, plantar nerves, and more rarely sciatic nerves, showed some unspecific lesions such as myelin whorls and ovoids within the outer Schwann cell cytoplasm, intra-axonal accumulations of polymorphous material, and single degenerating fibres. The pathogenetic mechanisms responsible for the non-specific lesions remain to be elucidated. Chlorphentermine was, in all respects, more potent than perhexiline. In general, the drug-induced lesions developing in the fibres of large nerve trunks were less dramatic when compared a) with the severe lipidosis known to occur in neuronal perikarya, and b) with the severe alterations known to develop in preterminal or terminal axon portions of rats kept under similar experimental conditions.

Animals↗
PubMed1983

Corneal lipidosis in rats treated with amphiphilic cationic drugs.

The purpose of this study was to investigate whether generalized lipidosis experimentally induced by cationic amphiphilic drugs in rats is regularly associated with lipidotic alterations in the cornea. After chronic oral treatment with chlorphentermine, iprindole, or tamoxifen all animals showed clear lipidosis-like alterations in corneal cells. After chronic oral treatment with chloroquine and quinacrine the results were variable and unpredictable; however, consistent lipidosis-like alterations were found when chloroquine was applied locally onto the cornea. The present results show that basically the cornea of rats is involved in drug-induced lipidosis. For toxicological studies it must be kept in mind, however, that the reactions of rat cornea may be unreliable and less marked than in the cornea of human beings.

Animals↗
PubMed1982

Histochemical evidence for lysosomal storage of acid glycosaminoglycans in splenic cells of rats treated with tilorone.

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 greater than 0.7 M, as compared to greater than 0.5 M for cartilage and greater than 0.9 M for mast cells. The storage materials in trabecular cells and macrophages were slightly less acidic than cartilaginous 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.

Animals↗
PubMed1982

Generalized lipidosis in newborn rats and Guinea pigs induced during prenatal development by administration of amphiphilic drugs to pregnant animals.

Pregnant rats and guinea pigs were treated throughout the second half of gestation with amphiphilic drugs (chlorphentermine, chlorcyclizine, chloroquine) known to induce generalized lipidosis. The offspring were sacrificed immediately after birth, and several tissues (lung, liver, kidney, spleen, pituitary gland, adrenal gland, spinal cord, hypothalamus) were examined by electron microscopy. Generalized lipidosis was found in the offspring of both species, albeit of lesser degree than in the mothers. The results show that fetal and adult tissues respond to lipidosis-inducing drugs in a qualitatively similar way; the quantitative differences found may be related to pharmacokinetic and cellular factors.

Adrenal Glands↗