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PubMed1981

The effect of phenobarbital on chlorphentermine-induced lipidosis-like alterations in renal tissue of adult and newborn rats.

Daily oral administration of 20 or 60 mg/kg chlorphentermine for 1 week produced a dose-related increase in the number of myeloid bodies in renal tissue of both adult and newborn rats. In adults myeloid bodies were present throughout the kidney while in neonates these bodies were found predominantly in the medullary region. Simultaneous administration of phenobarbital and either chlorphentermine dose resulted in a reduction in the number of myeloid bodies in kidneys of adults and newborns. Our data show that phenobarbital prevented the chlorphentermine-induced lipidosis in renal tissue and that newborns appear less sensitive than adults to the histopathologic action of anorectic on kidney.

Animals↗
PubMed1978

Renal and hepatic nucleic acid metabolism in neonates: relation to experimental duration, chlorphentermine dose as well as subsequent withdrawal.

Daily oral administration of either 20, 40 or 60 mg/kg chlorphentermine for 7 days significantly increased liver and kidney DNA levels, which were not elevated further even after a 3 week treatment period. Although cessation of drug administration for 3 weeks resulted in a return of hepatic DNA levels to control values, a rise in renal DNA was still observed after this withdrawal period. Whereas 20 mg/kg chlorphentermine for 7 days failed to markedly alter the incorporation of thymidine into kidney and liver DNA, significant enhancement was noted in neonates receiving 40 or 60 mg/kg drug and quantitatively greater incorporation occurred when the agent was given for 21 days. While a signficant augmentation in nucleic acids synthesis was seen 1 week after animals were removed from 40 or 60 mg/kg anorectic, a restoration to control levels occurred after a 3 week abstinence period. Treatment with 20 mg/kg for 1 week followed by withdrawal resulted in a significant rise in the incorporation of thymidine into renal and hepatic DNA. In contrast, drug administration for 3 weeks followed by 21 days abstinence resulted in a return to control levels in the incorporation of thymidine into kidney and liver DNA, except for renal tissue removed from 20 mg/kg. Our data demonstrate that the chlorphentermine-induced alterations in renal and hepatic DNA metabolism are dose-dependent, related to duration of exposure as well as reversible.

Animals↗
PubMed1988

Chlorphentermine may produce dual stimulus effects: a preliminary investigation.

1. Rats were trained to discriminate injections of either (+)-amphetamine (0.75 mg/kg) or (+/-)-fenfluramine (1.5 mg/kg) from saline in a two-lever drug discrimination task. 2. After stable discrimination performances were attained in each group, stimulus generalization studies were conducted with amphetamine, fenfluramine, and chlorphentermine. 3. Stimulus generalization (substitution) did not occur between amphetamine and fenfluramine when either drug was used as the training stimulus. 4. In contrast, both the amphetamine stimulus and the fenfluramine stimulus generalized completely to chlorphentermine. 5. Taken together, the results suggest that chlorphentermine may be capable of producing dual stimulus effects in animals.

Animals↗
PubMed1999

[Chloroquine- and chlorphentermin-induced lipidosis in rat retina].

BACKGROUND: The amphiphilic drugs chloroquine and chlorphentermine are known to cause lipidosis in the human and rat retina. METHODS: We treated femal albino Wistar rats orally with chloroquine for 12 weeks, followed by a period of 4 months with normal feed and another group with chlorphentermine for 4-16 weeks. The animals were submitted to electroretinography, and the retinae were prepared for histological investigations. RESULTS: Chloroquine caused severe lipidosis in the neuroretina and slight photoreceptor cell degeneration after 12 weeks of treatment. The b-wave was reduced to 30% of initial values. After withdrawal the lipidosis remitted, but the degeneration of the photoreceptor cell layer continued to progress. The a-wave and b-wave amplitudes were reduced to 25% and 16% of initial values, respectively. Chlorphentermine caused pronounced lipidosis in the pigment epithelium and less numerous in the neuroretina after 16 weeks; no photoreceptor cell degeneration was found. The b-wave was reduced to 80% of initial values, the a-wave appeared unaffected. CONCLUSION: Whether lipidosis is the primary cause of changes in the electroretinogram and of receptor cell degeneration is doubtful. Excessive lipid storage may be the cause of secondary changes. It is unlikely that lipidosis in pigment epithelium played a role.

Administration, Oral↗
PubMed1979

Effect of desmethylimipramine on the kinetics of chlorphentermine accumulation in isolated perfused rat lung.

A number of basic amines are preferentially accumulated by the lung and there is the possibility that drug interactions in this organ may be important in vivo. In this study, the kinetics of the accumulation process for chlorphentermine were examined in a "single pass" isolated perfused rat lung. Chlorphentermine (2.5 x 10-7-2.5 x 10-5 M) was rapidly taken up over the 10-min perfusion period, and the rate of uptake was well described by a biexponential equation. One component of the uptake was small in capacity and nonsaturable while the other was large in capacity and saturable. The smaller component could not be explained solely by distribution into total lung water. When desmethylimipramine (10-6-10-3 M) was added to the perfusate, it had little effect on the nonsaturable component but markedly affected the other; the initial velocity of uptake was decreased and the (negative) rate of change of uptake was increased with increased desmethylimipramine concentration. The data suggested that there were at least two mechanisms involved in uptake of chlorphentermine: a saturable transport process and tissue binding. It is not clear without further work whether the transport saturability is a mainfestation of a carrier-mediated process or of drug-induced membrane changes affecting diffusion.

Animals↗
PubMed1979

Effect of chlorphentermine on hormone content and function of the adrenal cortex in rats.

Amphiphilic drugs like chlorphentermine induce a generalized lipid storage disease upon chronic application. The adrenal cortex is among the organs most heavily affected. We therefore determined the urinary corticosterone excretion during the treatment of rats with chlorphentermine and the corticosterone content of the adrenals and its blood level at the end of the treatment period. In addition, the responsiveness of adrenal cortex was tested by application of ACTH. During treatment, the corticosterone excretion declined considerably. Both the corticosterone content of the adrenals and the plasma level were found depressed at the end of a treatment period of 8 weeks. The ACTH evoked response was also diminished. The results indicate that the chlorphentermine-induced lipidosis is associated with a reduced corticosterone production of the adrenal cortex of rats. At present it cannot be decided whether the cortical insufficiency is causally related to lipidotic alterations of the cortical cells, or whether it is caused or additionally influenced by alteration at a higher level, e.g. hypothalamic centers or anterior pituitary.

Adrenal Cortex↗
PubMedDate not supplied

Early changes in chlorphentermine myopathy of rat studied by freeze fracturing.

Chlorphentermine interferes with the metabolism of phospholipids. When administered to the rat in daily doses for 5 days, it causes necrosis of muscle fibers that are rich in mitochondria. Before the onset of necrosis, the following characteristics of freeze-fractured muscle preparations were observed: multilayered lipid globules and single-layered lipid membranes without membrane particles; different stages of exocytosis of lipid through the plasma membrane of the muscle fibers; and areas of plasma membrane that were devoid of particles of intramembranous proteins. These latter areas may arise secondary to exocytosis, to fusion of lipid vesicles with the plasma membrane, or to a direct action of chlorphentermine on the membrane. It is not known whether these areas give rise to membrane defects and fiber necrosis.

Animals↗
PubMed1976

Alterations in the neurohypophysis of rats treated with chlorphentermine or tricyclic antidepressants.

Rats were treated with several amphiphilic, cationic compounds that are known to cause generalized lipidosis (chlorphentermine, iprindole, 1-chloro-amitriptyline, clomipramine). After prolonged drug treatment the neurohypophysis showed severe morphologic alterations particularly in Herring bodies (HB), perivascular cells, and pituicytes. HBs displayed the following abnormalities: (a) great accumulation of autophagic vacuoles that contained neurosecretory granules (NSG); (b) numerous coarse osmiophilic conglomerates; (c) masses of multilamellated material; (d) reduced numbers of intact NSGs. Perivascular cells accumulated large lamellated inclusion bodies. Pituicytes contained membrane-bound crystalloid inclusion bodies. The noxious effect of chlorphentermine and l-chloro-amitriptyline was more pronounced than that of iprindole and clomipramine. The alterations in perivascular cells and in pituicytes are typical of drug-induced lipidosis. The lesions in HBs are tentatively explained as follows: HBs were previously proposed to be the sites of normally occurring intraaxonal disposal of excess neurosecretory material. The present experimental conditions interfere with this catabolic process. Incomplete digestion of the axo-plasmic constituents due for disposal might result in abnormal accumulation of NSG-containing autophagic vacuoles, osmiophilic conglomerates, and multilamellated material. This eventually leads to degeneration of HBs. The functional implications of the neurohypophysial lesions remain to be elucidated by functional experiments.

Animals↗
PubMed1975

Drug-induced phospholipidosis. II. Alterations in the phospholipid pattern of organs from mice, rats and guinea-pigs after chronic treatment with chlorphentermine.

In three species chronic treatment with the anorectic drug chlorphentermine causes a profound alteration of the phospholipid/lipid metabolism in the organism, resulting in an increase of the fractions of phospholipids and lipids, e.g. in lungs, livers and adrenals. The results are interpreted as drug-induced generalized phospholipidosis, which is caused by amphiphilic drugs, like chlorphentermine and others. Its extent depends on several factors, like content, pattern and turnover rate of phospholipids in different organs, and on the species.

Adrenal Glands↗
PubMed1983

Chlorphentermine-induced neonatal and maternal pulmonary phospholipidosis in rats.

Pregnant rats were treated on Days 16-20 of pregnancy with 30 mg/kg chlorphentermine hydrochloride (CP) or an equal volume of 0.9% NaCl. Females delivered on Day 21 and neonates were examined 12 hr postpartum. Electron micrographs showed the CP neonates to have lamellar inclusions, characteristic of drug-induced phospholipidosis in Type I and Type II cells, macrophages, and nonciliated bronchiolar epithelial cells of the lung. These inclusions were either unicentric, multicentric, or consisted of whorls of membranous material. The content of total phospholipids was increased in neonatal lung as a result of CP treatment. A decrease in the percentage of total phospholipid present as phosphatidylinositol plus phosphatidylserine and an increase in the content of disaturated phosphatidylcholine were found in neonatal lung as a result of maternal chlorphentermine treatment. In maternal lung, increases were seen in the content of total phospholipids, total phosphatidylcholine, disaturated phosphatidylcholine, and phosphatidylinositol plus phosphatidylserine. A decrease in the percentage of sphingomyelin was also found. The results of this study indicate that following prepartum maternal administration of CP morphological changes are accompanied by biochemical alterations which are consistent with the induction of phospholipidosis as observed in neonatal lung. These biochemical changes were different than those associated with the induction of this disorder in the maternal lung.

Animals↗
PubMed1977

The metabolism, distribution and elimination of chlorphentermine in man.

1 A gas-liquid chromatography procedure for the determination of chlorphentermine (I), N-hydroxychlorphentermine (II) and alpha,alpha-dimethyl-alpha-nitro-beta-(4-chlorophenyl)ethane (IV) in urine has been developed. Also methods are reported to determine conjugated II and the total N-oxidized metabolites of I, i.e. II, conjugated II, alpha,alpha-dimethyl-alpha-nitroso-beta-(4-chlorophenyl)ethane (III) and IV in urine. 2 The synthesis of alpha,alpha-dimethyl-alpha-nitroso-beta-(4-chlorophenyl)ethane (III) and its properties are reported. 3 The kinetics of urinary excretion of I and its metabolic products after the oral administration of I to a human subject on separate occasions have been studied. Under normal conditions of urinary pH, metabolism by N-oxidation was the main elimination route of I; acidifying the urine increased the urinary excretion of unchanged I at the expense of the N-oxidized products. 4 The importance of the N-oxidation metabolic route in the distribution of chlorphentermine (I) in man is discussed.

Adult↗
PubMed1975

Drug-induced foam cell reactions in rats, II. Chemical analysis of lipids stored in lungs and foam cells after treatment with chlorphentermine, 5-[p-(fluoren-9-ylidenemethyl)phenyl]-2-piperidineethanol (RMI 10.393) and 1-chloramitriptyline.

Lipidosis and foam cell reaction was induced in rat lungs by repeated administration of chlorphentermine, RMI 10.393 (=5-[p-(fluoren-9-ylidenemethyl)phenyl]-2-piperidineethanol), and 1-chloramitriptyline. Foam cell and lung lipids were extracted and separated in classes by thin-layer chromatography. Phospholipids were determined by phosphorus analysis, while neutral lipids were measured densitometrically. In lungs of drug-treated rats lecithin, phosphatidyl glycerol, phosphatidic acid, phosphatidyl inositol and free fatty acids accumulated in varying amounts. All other lipids were present in normal or reduced concentrations. Foam cells of chlorphentermine- and RMI 10.393-treated rats contained mainly phospholipids, i.e. lecithin and only small amounts of neutral lipids, i.e. cholesterol. Foam cells induced by 1-chloramitriptyline contained besides phospholipids also large amounts of neutral lipids, i.e. cholesterol, free fatty acids and cholesterol esters. This study and recent reports of others show that certain drugs produce a generalized metabolic disturbance characterized by accumulation of various lipids in several tissues. The distribution patterns of lipids induced by various drugs may differ considerably. This indicates that several biochemical mechanisms may be involved in the pathogenesis of drug-induced lipidosis.

Amitriptyline↗
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↗
PubMed1981

Impairment of renal function in rats with generalized lipidosis as induced by chlorphentermine.

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.

Animals↗
PubMed1995

In vivo and in vitro reversibility of chlorphentermine-induced phospholipidosis in rat alveolar macrophages.

Chlorphentermine (CP) is a cationic, amphiphilic drug (CAD) that has been studied widely for its ability to induce phospholipidosis, a disorder characterized by excessive accumulation of cellular phospholipid and ultrastructural development of lysosomal lamellar bodies (LLBs) in the cell. The accumulation of inducing drug correlates with increasing phospholipids. In the present study, we examined the reversibility of this disorder in rat alveolar macrophages (AMs) following a 7-day treatment (30 mg/kg/day, ip). The reversibility of phospholipidosis was examined under in vivo conditions and under in vitro conditions in cell cultures for a period of up to 12 days. There was a marked reduction in cellular CP levels and phospholipid content after 4 days of recovery, both in vivo and in vitro; however, there was no indication of significant loss of LLBs. Beyond this time point, ultrastructural recovery from phospholipidosis lagged behind the biochemical recovery temporally and was somewhat less rapid in vitro than in vivo. By 12 days of recovery, AMs from both groups had recovered biochemically, but a moderate level of LLBs was still present in some AMs in the in vitro recovery group. The results of this study indicate that there are more similarities than differences when comparing the recovery of phospholipidotic cells in vitro to that occurring in vivo. We conclude that the use of cell cultures may prove valuable in studying the reversibility of CAD-induced phospholipidosis.

Animals↗
PubMed1976

Ultrastructure and biochemical studies of rat CNS and viscera after subcutaneous injection of chlorphentermine.

Ultrastructural and biochemical studies were carried out on three groups of experimental models which were induced by a single subcutaneous daily dose of 10 to 40 mg./kg. body weight of chlorphentermine hydrochloride. The first group consisted of 20 young adult rats which were sacrificed at intervals of from one to four weeks. The liver and lungs showed concentrically arranged memberanous bodies in the hepatocytes and alveolar cells during the first week after the first injection, while the CNS and pancreas showed no ultrastructural alterations. During the fourth week, the pancreas displayed abnormal cytoplasmic inclusion bodies in the A and B cells of the islets of Langerhans as well as in the exocrine portion. The brain showed various neuronal alterations at four weeks which consisted of irregular dense bodies to well-developed membranous structures which were similar to those of Tay-Sachs disease. Biochemically, thin layer chromatograms showed that the major ganglioside fraction in the brain at four weeks had an RF value similar to that of GM1-ganglioside. In an analysis of the total N-acetyl neuraminic acid the brains in the experimental group contained 90.9% GM1-gandlioside as compared with 44% in the controls. The total and fractions of phospholipids in the brains and livers of the experimental animals were within normal limits.

Animals↗
PubMed1976

Alterations in peripheral nerves of rats treated with chlorphentermine or with iprindole.

This study deals with the effects of two amphiphilic lipidosis-inducing drugs (chlorphentermine, iprindole) upon the ultrastructure of peripheral nerves of rats. After prolonged drug treatment the preterminal and terminal axoplasm of motor and sensory nerves within skeletal muscles contain numerous abnormal inclusions (osmiophilic conglomerates, autophagic vacuoles, lamellated bodies). By contrast, the axons within large peripheral nerves are little effected. The present observations are tentatively interpreted as resulting from interference with catabolic processes involved in the normal turnover of axoplasmic constituents at the nerve terminal. The exact pathogenesis and the functional significance of these alterations remain to be elucidated.

Animals↗
PubMed1976

Retinal lipidosis in albino rats treated with chlorphentermine and with tricyclic antidepressants.

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, 1-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 nondigestible 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.

Amitriptyline↗