Biomedical subjects
Publications and source records attributed to R Lüllmann-Rauch.
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Chronic administration of certain cationic amphiphilic drugs to rats and other species induces generalized lysosomal storage of polar lipids. In rat, retinal pigment epithelium belongs to the tissues which are most susceptible toward this adverse drug action. Drug-induced lipidosis in retinal epithelium is characterized ultrastructurally by the occurrence of numerous cytoplasmic inclusion bodies with a crystalline-like internal structure. Freeze-fracture images of such inclusions indicate that they consist of phospholipids aggregated in a hexagonal phase. The quantitative and structural uniformity of lipidosis in retinal pigment epithelial cells appears to reflect the uniformity of the lipid load which is physiologically imposed on the digestive apparatus of the epithelium due to the phagocytosis of photoreceptor membranes. The pathophysiological significance of drug-induced lipidosis in pigment epithelium remains to be clarified.
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The present paper describes an animal model of lysosomal glycogenosis as induced by a competitive inhibitor of alpha-glucosidase. Rats received intraperitoneal injections of the inhibitor, a pseudotetrasaccharide (Acarbose, Bay g 5421); liver tissue was examined by light and electron microscopy. Substrate-histochemical and enzyme-cytochemical methods were used to demonstrate intralysosomal glycogen storage within hepatocytes and Kupffer cells. The cytological picture closely resembled that occurring in glycogenosis type II (Pompe's disease) of humans. After cessation of drug treatment, the glycogen storage was slowly reversible. The present results point to the physiological role of the lysosomal apparatus for intracellular glycogen turnover. On the cellular level, this experimentally induced glycogenosis may be useful as a model of Pompe's disease.
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The purpose of this work was to study the impact of experimentally induced lipidosis upon renal function. Rats were orally treated up to 12 weeks with the anorectic drug chlorphentermine at dosages of 20 and 50 mg/kg, respectively. During the course of treatments the following parameters were determined: plasma urea level, creatinine clearance, ability of the kidneys to concentrate the urine after acute deprivation of drinking water, and to dilute the urine after acute water load. Morphological examination confirmed generalized lipidosis affecting kidney and many other organs. Chronic treatments with both drug dosages caused a rise of plasma urea level. Treatment with the high dosage caused a significant reduction of creatinine clearance and significant impairment of both abilities to concentrate and to dilute the urine. The findings demonstrate that serve generalized lipidosis as induced by high doses of chlorphentermine is associated with significant impairment of renal function.
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.
This study was aimed at the question of whether or not the antidepressant zimelidine, which is an amphiphilic cationic compound, can induce generalized lipidosis in animals. Rats were chronically treated with high oral doses (80 mg/kg) of the drug, and several organs were examined by light and electron microscopy. Lipidosis-like cellular alterations of considerable degrees were observed in lung, adrenal cortex and lymphatic tissue. Only mild lysosomal alterations were found in hepatocytes, adrenal medulla, retinal pigment epithelium and in peripheral and central nerve cell perikarya. The results show that zimelidine induces generalized lipidosis in rats although of mild degree when compared with some other amphiphilic cationic drugs.
The ultrastructure of cytoplasmic inclusions, which characterize experimental lipidosis as induced by several amphiphilic cationic drugs, was studied by means of freeze-fracturing and thin-sectioning. Retinal and adrenal tissues of rats chronically treated with high oral doses of chlorphentermine were used. In thin sections the cytoplasmic inclusions, which were previously shown to represent lysosomes overloaded with polar lipids, exhibit lamellated or lattice-like internal patterns. The present freeze-fracture observations are interpreted as to indicate that the lamellated inclusions contain polar lipids in the lamellar phase, whereas those with lattice-like patterns contain polar lipids in a hexagonal phase.
Several cationic amphiphilic drugs, each of which is known to induce generalized lipidosis in rats, were compared with respect to their cytological effects on rat choroid plexus epithelium. Chloroquine induced large cytoplasmic vacuoles, whereas the other drugs (quinacrine, 4,4'-diethylaminoethoxyhexestrol, chlorphentermine, iprindole, 1-chloro-amitriptyline, clomipramine) caused formation of lamellated or crystalloid inclusions as usually seen in drug-induced lipidosis. The ultrastructure of the chloroquine-induced vacuoles suggested storage of water-soluble materials (polar lipids and/or non-lipid materials) in addition to non-water-soluble polar lipids.
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Treatment of taipoxin with p-bromophenacyl bromide resulted in modification of single histidine residues in the alpha and beta subunits. The modification decreased the neurotoxicity (lethality) 350-fold, but the inhibitory action on high-affinity choline transport was reduced only threefold. The phospholipase activity and Ca2+-association constants for taipoxin and its subunits were determined. A model for the neurotoxicity of taipoxin indicates the alpha subunit as the ultimate cause of the disruption of synaptic transmission.
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The antianginal drug amiodarone (an amphiphilic cationic compound) causes a keratopathy in humans. In the present investigation the cytologic effects of amiodarone on ocular tissues of rats were studied. Ultrastructural alterations, which are typical of human keratopathy and characteristic of drug-induced lipidosis, could be experimentally reproduced in rats by local application of amiodarone. Repeated oral administration of high drug doses induced lipidosis-like alterations in many ocular cell types, particularly in retinal pigment epithelium. It is concluded that amiodarone has the potency to induce generalized lipidosis in rats, as do several other previously investigated amphiphilic cationic drugs. It is tentatively suggested that amiodarone-induced corneal alterations in humans might equally be interpreted as part of a generalized lipidosis.
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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.