ABSTRACT
INTRODUCTION: Alcohol has long been suspected to be a triggering and precipitating factor of psoriasis. Alcohol misuse is common in patients with moderate-to-severe psoriasis and appears to impair treatment outcome. AREAS COVERED: In this article, the authors review the available data regarding the metabolic and toxicological interactions between anti-psoriasis systemic drugs and ethanol and/or alcoholic beverages. Special attention is given to the influence of alcohol consumption on the hepatotoxic risk of some anti-psoriasis drugs. The article was prepared using a MEDLINE literature search. EXPERT OPINION: The available knowledge highlights the existence of a few significant pharmacological interactions, such as the reduced exposure to cyclosporine by red wine, the possible increase of cyclosporine levels following a heavy acute alcohol intake, and, especially, the conversion of acitretin to etretinate, in the presence of ethanol, with important implications in females of child-bearing potential. There are limited data on the contributing role of alcohol in the hepatotoxicity induced by some anti-psoriasis drugs and the existing information on this topic is still controversial. However, further investigation is needed to assess the relevance of interactions between alcohol consumption and drug therapy for psoriasis, under both pharmacological and toxicological perspectives. Long-term prospective studies on large cohorts of patients are warranted to disclose the actual significance of such potential interactions in clinical practice.
Subject(s)
Acitretin/toxicity , Alcohol Drinking/adverse effects , Ethanol/adverse effects , Etretinate/toxicity , Keratolytic Agents/toxicity , Psoriasis/drug therapy , Acitretin/metabolism , Acitretin/pharmacokinetics , Administration, Topical , Alcohol Drinking/metabolism , Chronic Disease , Ethanol/metabolism , Etretinate/metabolism , Etretinate/pharmacokinetics , Folic Acid Antagonists/pharmacokinetics , Folic Acid Antagonists/toxicity , Humans , Keratolytic Agents/pharmacokinetics , Skin/drug effects , Skin/pathologyABSTRACT
The toxicity of Etretinate, a retinoid compound, on the male reproductive system was studied in male rats. The drug was administered for four weeks at the dose levels of 0 (control: Vehicle, Peanut oil), 5 and 25 mg/kg/day. The animals were then allowed to mate, and their male reproductive functions and organs were examined in detail. No significant changes due to toxicity were observed in male reproductive functions and organs in the 5 mg/kg/day group after the 4-week treatment. In contrast, males in the 25 mg/kg/day group showed drug-related changes in their reproductive performance (decrease of mating ability and fertility rate), testosterone blood level, sperm head counts, sperm viability and number in the caudal epididymis, organ weight and in the histopathology of their reproductive organs (atrophy of seminiferous tubules, necrosis of spermatocytes and spermatids, vacuolation of nuclei of spermatocytes and spermatids). Even though Etretinate belong to the retinoid group of compounds, the changes seen in the 25 mg/kg/day group were almost the same as those observed in Vitamin A-deficient animals. In conclusion, there is a correlation between changes due to toxicity observed for parameters of male fertility and for histopathological evaluation of the testis of rats that receiving high dose, treatment with Etretinate for 4 weeks.
Subject(s)
Etretinate/toxicity , Fertility/drug effects , Animals , Body Weight/drug effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Eating/drug effects , Etretinate/administration & dosage , Female , Hormones/blood , Keratolytic Agents/administration & dosage , Keratolytic Agents/toxicity , Longevity/drug effects , Male , Organ Size/drug effects , Pregnancy , Rats , Rats, Sprague-Dawley , Sperm Count/drug effects , Sperm Head/drug effects , Spermatozoa/drug effects , Testis/drug effects , Testis/pathologyABSTRACT
Etretinate, a synthetic retinoid, is a potent teratogen. It has previously been shown that acute exposure of gestational day 8 (equivalent to human week 4 post-fertilization) C57BL/6J mouse embryos to this retinoid results in a spectrum of abnormalities that are recognized as constituting caudal regression (dysgenesis). These defects, which include spina bifida, imperforate anus, genitourinary anomalies, omphalocele and limb anomalies, result from a major insult to the primitive streak, that is the gastrulation process. Developmental stages present early on gestational day 9 in mice represent the final stages during which the primitive streak contributes to the trunk of the embryo and, therefore, the last opportunity for abnormalities within the realm of caudal regression to be induced. In fact, acute etretinate exposure on gestational day 9 resulted in anal and urethral atresia, bladder and ureteral dilatation, and tail deficiencies as observed in 251 near-term fetuses in this study. To examine in further detail the gestational day 9 etretinate induced urogenital and anal abnormalities and their pathogenetic basis, analyses were conducted using scanning electron microscopy, light microscopy, antegrade cystourethrograms and a vital staining technique as early as 6 hours following maternal drug administration. It appears that diminution of the caudal cell populations, including those of and those surrounding the cloaca, at this critical stage of embryogenesis accounts for the observed phenotype. We propose that anal and urethral atresia temporally represents the end of the caudal regression (dysgenesis) syndrome.
Subject(s)
Abnormalities, Drug-Induced/etiology , Cloaca/abnormalities , Etretinate/toxicity , Urogenital Abnormalities , Abnormalities, Drug-Induced/embryology , Abnormalities, Multiple/chemically induced , Abnormalities, Multiple/embryology , Animals , Anus, Imperforate/chemically induced , Cloaca/embryology , Female , Gestational Age , Mice , Mice, Inbred C57BL , Microscopy, Electron, Scanning , Pregnancy , Tail/abnormalities , Urethra/abnormalities , Urinary Bladder/abnormalities , Urogenital System/embryologyABSTRACT
When female SD rats were continuously treated with Etretinate throughout pre-mating, gestation, and lactation periods, the resulting F1 pups exhibited low viability and inhibition of somatic growth after birth (Hummler et al., 1981). Nevertheless, these pups showed no notable change in body weight and external appearance at birth. We used the cross-fostering (between control and treated groups) method and investigate the neonatal viability and the growth hormonal changes in order to assess which treatment period of gestation or lactation was mainly involved in these effects and what changes were actually induced in the F1 pups. The results showed that low viability and inhibition of somatic growth after birth were mainly related to treatment during the gestation period, and these effects were augmented by treatment during the lactation period. Serum GH and IGF-I levels were increased on day 21 in F1 pups groups in which inhibition of somatic growth was observed. These results indicated that treatment with Etretinate during the gestation period might induce a decrease in the number of receptors of GH and IGF-I or other changes, such as a poor-response in target tissues due to a down-regulation, with an increase of serum GH and IGF-I levels.
Subject(s)
Etretinate/toxicity , Fetal Viability/drug effects , Growth/drug effects , Lactation/drug effects , Pregnancy, Animal/drug effects , Animals , Female , Growth Hormone/blood , Insulin-Like Growth Factor I/metabolism , Liver/drug effects , Male , Organ Size/drug effects , Pituitary Gland/drug effects , Pregnancy , Rats , Rats, Sprague-DawleyABSTRACT
Chemoprevention is a clinical strategy to block or reverse carcinogenesis before the development of invasive cancer. Studies of chemoprevention in the lungs and upper aerodigestive tract have relied on the field carcinogenesis hypothesis, which predicts that diffuse epithelial injury will result from exposure of that epithelium to carcinogens. This hypothesis is supported by the frequent occurrence of multiple primary tumors within the exposed field. In addition, the understanding of carcinogenesis as a multistep process supports the use of interventions in damaged epithelium before the development of clinically invasive cancer. Current efforts are focused on applying to chemoprevention studies the increasing knowledge of the molecular events in carcinogenesis. In our program, clinical trials in lung and head and neck chemoprevention have focused on individuals with evidence of field carcinogenesis, i.e., a history of previous epithelial cancer or the presence of premalignant lesions. These trials include studies to develop clinically applicable intermediate markers of carcinogenesis and large Phase III trials to evaluate the efficacy of the retinoid isotretinoin in preventing second primary tumors following head and neck or lung cancers.
Subject(s)
Anticarcinogenic Agents/therapeutic use , Head and Neck Neoplasms/prevention & control , Lung Neoplasms/prevention & control , Mouth Neoplasms/prevention & control , Retinoids/toxicity , Retinoids/therapeutic use , Anticarcinogenic Agents/toxicity , Diterpenes , Etretinate/therapeutic use , Etretinate/toxicity , Humans , Isotretinoin/therapeutic use , Isotretinoin/toxicity , Leukoplakia/pathology , Retinyl Esters , Vitamin A/analogs & derivatives , Vitamin A/therapeutic useABSTRACT
Systemic use of retinoids is common in the treatment of various dermatological disorders. Blepharitis and conjunctivitis have been reported in 20-45% of the patients following systemic treatment with 13-cis-retinoic acid. Our purpose was to study the histopathological changes in the eyelids caused by long-term systemic treatment of female New Zealand rabbits with isotretinoin (2 mg/kg) and etretinate (2 mg/kg). The histopathological evaluation showed degenerative changes in the meibomian gland acini, leading to cell necrosis and a decrease in the basaloid cells lining the acini walls. No evidence of acute or chronic inflammatory reaction was noted.
Subject(s)
Etretinate/toxicity , Isotretinoin/toxicity , Meibomian Glands/drug effects , Administration, Oral , Animals , Capsules , Etretinate/administration & dosage , Eyelids/pathology , Female , Isotretinoin/administration & dosage , Meibomian Glands/pathology , Necrosis , RabbitsABSTRACT
Treatment of pregnant Sprague-Dawley rats with retinoic acid or etretinate pregnancy day 8.5 to 9.0 resulted in craniofacial defects in 100% of the embryos. A morphologic investigation of the malformations occurring in the ear was performed. Outer ears were missing, microtic, low-placed, and dorsally situated. External acoustic meatus was short or absent. Middle ear structures were delayed in differentiation, middle ear ossicle primordia were hypoplastic and malformed, the stapedial artery and facial nerve were hypoplastic, and their relation to the stapes was variable. In the inner ear, the otic capsule was thick, the cochlea had fewer turns and the semicircular ducts showed poor differentiation.
Subject(s)
Abnormalities, Drug-Induced/etiology , Ear/abnormalities , Etretinate/toxicity , Fetus/drug effects , Tretinoin/toxicity , Animals , Ear/embryology , Ear, External/abnormalities , Ear, External/embryology , Ear, Inner/abnormalities , Ear, Inner/embryology , Ear, Middle/abnormalities , Ear, Middle/embryology , Female , Fetal Death/chemically induced , Pregnancy , Rats , Rats, Inbred StrainsABSTRACT
A single application of 17 micrograms/kg or 8.7 mg/kg all-trans-[10,11-3H2]-retinoic acid dissolved in acetone to shaved dorsal hamster skin resulted in rapid absorption and dose-dependent rates of elimination. An equation describing a two-compartment open model with a very brief lag time and first-order uptake and elimination was used to describe the central plasma compartment kinetics. Unchanged all-trans-retinoic acid represented less than or equal to 4% of the total circulating radio-activity. Peak circulating concentrations of parent all-trans-retinoic acid were less than those observed after an equivalent oral dose, but prolonged absorption from the skin appears to contribute to high total bioavailability of topical retinoid. Topical administration to intact skin of up to three consecutive doses of 10.5 mg/kg/d all-trans-retinoic acid or a single 5 mg/kg dose of etretinate (Ro 10-9359) during a critical stage of embryogenesis in hamsters caused erythema and/or dose-dependent epidermal hyperplasia at the site of application, but failed to induce a significant teratogenic response. Topical application of 0.01-1.0 mg/kg arotinoid Ro 13-6298 resulted in dose-dependent mucocutaneous toxicity and an increase in the numbers of dead embryos and malformed offspring. The marked skin toxicity and attenuated concentrations in maternal blood, compared to the oral route, limit the amounts of retinoid that can reach the hamster embryo. It is thus more important to compare the retinoid systemic values (absorbed dose) than it is to compare the oral or topical (applied) dose, when interpreting the results of conventional teratogenicity bioassays. The data suggest that in the human it is skin toxicity that limits the amounts of retinoid that can be applied and subsequently reach the embryo. In the rodent, overt skin toxicity under continued dosing could increase the amounts of retinoid penetrating the skin and reaching the embryo.
Subject(s)
Embryo, Mammalian/drug effects , Skin Absorption/drug effects , Tretinoin/pharmacokinetics , Administration, Oral , Administration, Topical , Animals , Antineoplastic Agents/toxicity , Benzoates/toxicity , Cricetinae , Dose-Response Relationship, Drug , Embryo, Mammalian/physiology , Etretinate/toxicity , Female , Maternal-Fetal Exchange/physiology , Mesocricetus , Pregnancy , Retinoids/toxicity , Skin/drug effects , Skin/metabolism , Skin Physiological Phenomena , Tretinoin/administration & dosage , Tretinoin/toxicityABSTRACT
Sprague-Dawley female rats were treated with a single oral dose of 0 (vehicle), 10, or 25 mg/kg of etretinate (ET), an aromatic retinoid, on gestation day 6, 7, or 8. While treatment on day 8 with both dosages of ET was highly teratogenic, no evidence of embryotoxicity, considered to be treatment related, was observed when the same doses were administered on day 6 or 7. We concluded that the rat embryo is not susceptible to teratogenic effects of ET on gestation day 6 or 7 and that day 8 is the earliest susceptible period for ET teratogenesis. This may well be true of retinoids as a class since we have observed similar results for all-trans- and 13-cis-retinoic acids (unpublished findings). In another study, mated rats were treated with a single oral dose of ET on day 8. No evidence of embryotoxicity was observed at dosages of 1, 3, and 6 mg/kg; in contrast, treatment with 10, 15, or 25 mg/kg of ET resulted in an increasingly greater number of malformed fetuses and resorptions. Plasma concentrations of ET and three metabolites [acitretin (AC), 13-cis-etretinate (13-cis-ET), and 13-cis-acitretin (13-cis-AC)) were determined in mated rats given a single oral non-teratogenic (3 or 6 mg/kg) or teratogenic (10 or 25 mg/kg) dose of ET on gestation day 8. The AUC0----24hr values of ET and AC, the major metabolite and suspected proximal teratogen, were roughly proportional to the administered dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Etretinate/toxicity , Maternal-Fetal Exchange , Teratogens , Acitretin , Animals , Dose-Response Relationship, Drug , Etretinate/blood , Etretinate/pharmacokinetics , Female , Fetus/drug effects , Male , Pregnancy , Rats , Rats, Inbred Strains , Tretinoin/analogs & derivatives , Tretinoin/blood , Tretinoin/metabolismABSTRACT
Vitamin A and synthetic retinoids have recently been used increasingly in a variety of health related concerns. Hepatic toxicity is an uncommon but serious side-effect of several Vitamin A derivatives which may lead to cirrhosis. This review will focus on the clinical and pathologic findings of hepatic involvement in chronic hypervitaminosis A and on the evidence concerning the potential hepatotoxicity of currently available synthetic retinoids.
Subject(s)
Chemical and Drug Induced Liver Injury/etiology , Etretinate/toxicity , Hypervitaminosis A , Isotretinoin/toxicity , Liver/drug effects , Chemical and Drug Induced Liver Injury/pathology , Etretinate/pharmacokinetics , Female , Humans , Hypervitaminosis A/etiology , Hypervitaminosis A/pathology , Isotretinoin/pharmacokinetics , MaleABSTRACT
Etretinate (Tegison, Tigason), a retinoid used for the treatment of skin disorders such as psoriasis, was shown to teratogenic in the human. Because of the long terminal half-life of this drug (100 days), considerable plasma levels of etretinate and its main metabolite, etretin (acitretin), were observed for up to 2 years following discontinuation of therapy. We have therefore investigated, in a newly developed animal model, the potential teratogenic risk of such persisting levels of these aromatic retinoids. Etretinate was administered by intragastric infusion throughout organogenesis in the mouse (day 8-15) via subcutaneously implanted osmotic minipumps connected to external reservoirs containing oily solutions of the drug. Dose-dependent developmental effects were found, the fetal weight decreased and the resorption rate and incidence of major malformation increased. A dose of 0.84 mg/kg/day resulted in retinoid-specific defects, in particular shortening of the limbs and cleft palate. This low dose infused resulted in mean etretinate concentrations of 6.5 ng/ml maternal plasma and 12.5 ng/g embryo (measured on days 10 and 12 of gestation). The corresponding concentrations of the metabolite etretin were 38 ng/ml plasma and 95 ng/g embryo. Our results emphasize the high teratogenic risk of relatively low, persisting concentrations of etretinate and etretin such as those observed after discontinuation of human therapy, because the area of the concentration-time curve is likely to be the decisive parameter in regard to teratogenesis.
Subject(s)
Abnormalities, Drug-Induced/etiology , Embryonic and Fetal Development/drug effects , Etretinate/toxicity , Tretinoin/analogs & derivatives , Acitretin , Animals , Etretinate/administration & dosage , Etretinate/pharmacokinetics , Female , Infusion Pumps, Implantable , Maternal-Fetal Exchange , Mice , Models, Biological , Pregnancy , Tretinoin/bloodABSTRACT
A series of branchial arch malformations was induced in 618 embryos from 72 pregnant rats by a single intraperitoneal injection of 10 mg/kg etretinate at 8.5 days of gestation. The litters developed several malformations, including microtia, low set and dorsally placed outer ears, defective middle ear ossicles, short cochleas, defectively differentiated Meckel's cartilages, micrognathia, rudimentary malar bones, lateral facial clefts, fistulas and skin tags, all of which were similar to Treacher Collins' syndrome in man. The defects were accompanied by a pathological differentiation pattern of various isoenzymes in maxillary and mandibular processes. These isoenzymes could be detected in amniotic fluid from the 9th to the 20th days of pregnancy and showed a pathological differentiation pattern here as well. We conclude that a teratogenically induced syndrome affecting the first and second branchial arches is accompanied by a pathological differentiation pattern that can be traced by determinations of isoenzymes in the branchial arches as well as in amniotic fluid.
Subject(s)
Clinical Enzyme Tests , Etretinate/toxicity , Isoenzymes/analysis , Mandibulofacial Dysostosis/diagnosis , Prenatal Diagnosis , 4-Nitrophenylphosphatase/analysis , Alkaline Phosphatase/analysis , Amniotic Fluid/enzymology , Animals , Creatine Kinase/analysis , Electrophoresis, Polyacrylamide Gel , Female , Fructose-Bisphosphate Aldolase/analysis , Isoelectric Focusing , Jaw/enzymology , L-Lactate Dehydrogenase/analysis , Male , Mandibulofacial Dysostosis/chemically induced , Naphthol AS D Esterase/analysis , Phosphoglycerate Mutase/analysis , Rats , Rats, Inbred Strains , TeratogensABSTRACT
Developmental toxicity of the anti-psoriatic drug etretinate (Tegison) and some features of its metabolic conversion to etretin and isoetretin were investigated in in vivo and in vitro teratogenesis bioassays. We found that a single dose of etretinate administered orally to pregnant mice on day 11 of gestation was a potent teratogen (ED50 = 26 mg/kg). Etretin (acitretin, Neotigason), given as a single dose, was about 8-fold less active as a teratogen than etretinate. A ring substituted congener of etretinate, Ro 11-4768, was essentially inactive under similar conditions. Although the mechanisms which operate to make Ro 11-4768 inactive in teratogenesis are unknown and intriguing, it is suggested that the differences between etretinate and etretin may be dependent on individual pharmacokinetic characteristics. The in vitro chondrogenesis bioassay confirmed previous reports that the presence of an acidic endgroup was necessary for suppression of chondrogenesis, and that on that basis etretin was an active inhibitor of chondrogenesis, whereas etretinate was not. Introduction of esterase into the culture medium resulted in complete hydrolysis of etretinate and a quantitative conversion to acid congeners sufficient to account for an appropriate suppression in chondrogenesis. Although limb bud cells were virtually incapable of converting etretinate to etretin in the absence of exogenous esterase, they did influence the metabolism so that in the presence of esterase, isoetretin rather than etretin was the major endproduct of etretinate hydrolysis. Since etretinate therapy endangers the conceptus for a prolonged period of time even after cessation of therapy, further studies are necessary to determine the nature and the extent of hazard posed by the storage and/or metabolism of etretinate.
Subject(s)
Etretinate/analogs & derivatives , Etretinate/metabolism , Retinoids/toxicity , Teratogens , Tretinoin/analogs & derivatives , Acitretin , Animals , Biotransformation , Cartilage/physiology , Cell-Free System , Chromatography, High Pressure Liquid , Esterases/metabolism , Etretinate/toxicity , Female , Fetus/drug effects , Male , Mice , Mice, Inbred ICR , Pregnancy , Tretinoin/toxicityABSTRACT
Etretinate is an aromatic retinoid extensively used on Dermatology. Its toxic effects, however, reduce its application from a clinical point of view. In the present paper, we study etretinate intoxication of 48 growing Wistar rats. The intoxication was for 12 weeks using etretinate doses of 0.5 and 6 (mg/kg)/day. The concentrations of etretinate in plasma and liver were determined. Total seric cholesterol and triglyceride concentrations were analyzed. Structural and ultrastructural histological studies of liver samples were carried out. Continuous etretinate ingestions seem to produce an alteration in the detoxication of enzymatic complexes in the growing rats with both the concentrations, due to the increase in etretinate blood plasma observed during the study. There is a relationship between the etretinate dose and its blood plasma concentration and toxic effect, but there is not with etretinate concentration in the liver. The blood plasma concentration of cholesterol and triglycerides is not related to histological liver lesions. The histological study confirms hepatotoxicity with both doses. Nevertheless, the anatomopathological lesions observed do not seem to be related to the blood plasma and liver etretinate concentrations.
Subject(s)
Etretinate/toxicity , Animals , Chemical and Drug Induced Liver Injury/pathology , Cholesterol/blood , Chromatography, High Pressure Liquid , Etretinate/analysis , Etretinate/blood , Indicators and Reagents , Liver/chemistry , Liver/pathology , Microscopy, Electron , Rats , Rats, Inbred Strains , Triglycerides/bloodABSTRACT
Small lipid droplets, the so-called liposomes, can serve as drug carriers and can in theory be targeted directly at diseased tissue. Thus, comparatively smaller quantities of drugs than usual are necessary. However, liposomes are recognized by the immune system and are absorbed by the reticuloendothelial system and therefore also by the Kupffer cells in the liver. These cells are storage compartments for esterified vitamin A. As about 80% of the liposomes are metabolized in the liver, retinoids form a pool for substances transported with retinoid-binding proteins. Whether retinoids reach the retina via direct liposome contact or through the endocytotic process is still not clear. In rabbits, however, retinoids applied in small unilamellar liposomes (SUV) produce photoreceptor malfunctioning (isotretinoin and etretinate) and photoreceptor outer segment damage with an increase in phagocytotic activity of the retinal pigment epithelium (etretinate).
Subject(s)
Etretinate/administration & dosage , Isotretinoin/administration & dosage , Retina/drug effects , Drug Carriers , Etretinate/toxicity , Female , Infusions, Intravenous , Isotretinoin/toxicity , LiposomesABSTRACT
Multiple actinic keratoses (MAK) are premalignant lesions that may produce a significant treatment problem not always controllable by destructive therapy. Etretinate therapy has been shown to produce both prophylactic and therapeutic effects on premalignant epithelial tumors of mice. Results are presented on an 8-month double blind crossover trial (4 months placebo/4 months etretinate, randomly assigned) in 15 patients with severe MAK. Fourteen patients improved significantly on etretinate, whereas five of six patients who had placebo in the first 4-month period became worse as measured by the number of lesions and diameter of larger lesions. However, eight of nine patients who had placebo in the second 4-month period (ie, following etretinate therapy) showed no significant increase in the number of actinic keratoses, suggesting that etretinate may prevent the appearance of new lesions during, and for some time after, its administration. Moderate dose-dependent mucocutaneous side effects were frequent. It is proposed that an annual 3-month course of etretinate may help control severe MAK patients, minimizing the need for destructive therapies.
Subject(s)
Etretinate/therapeutic use , Keratosis/prevention & control , Precancerous Conditions/prevention & control , Skin Neoplasms/prevention & control , Adult , Aged , Clinical Trials as Topic , Etretinate/toxicity , Female , Humans , Keratosis/drug therapy , Keratosis/etiology , Male , Middle Aged , Precancerous Conditions/drug therapy , Random Allocation , Ultraviolet RaysABSTRACT
Retinoic acid has the ability to act as either a weak first stage promoter or a weak complete promoter in the initiation-promotion protocol for skin carcinogenesis in the SENCAR mouse. The retinoid analog RO-10-9359 lacks this tumor promoting activity. Both retinoids however inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion. Additional comparisons revealed that retinoic acid alone can induce dark keratinocytes, a characteristic of tumor promoters, while RO-10-9359 cannot. Retinoic acid but not RO-10-9359 can induce an immediate chemiluminescence response in human polymorphonuclear cells. Both retinoids, however, inhibit a TPA-induced response. Since the chemiluminescence response is believed to be due to oxygen free radical generation, the data suggest that the ability of retinoic acid but not RO-10-9359 to promote tumors and induce dark cells may be due to initial oxidative reactions at the cell membrane.
Subject(s)
Etretinate/toxicity , Skin Neoplasms/chemically induced , Tretinoin/toxicity , Animals , Female , Keratins/metabolism , Luminescent Measurements , Mice , Neutrophils/drug effects , Neutrophils/physiology , Ornithine Decarboxylase/metabolism , Skin Neoplasms/enzymology , Skin Neoplasms/pathology , Tetradecanoylphorbol AcetateABSTRACT
Repeated ingestion of high doses of retinoids cause the so-called hypervitaminosis A syndrome. In rats the main symptoms are weight loss, alopecia, erythema, desquamation of the skin, and alterations of the skeletal system, including bone fractures. In the present study, three retinoids (Ro 15-1570, arotinoid ethylsulfone, 6 mg/kg; retinoic acid, 100 mg/kg and etretinate, 50 mg/kg) were administered orally to rats for 1 and 2 weeks, respectively, to six male and six female rats/group. All the above changes were induced by all three retinoids, with the exception that the arotinoid ethylsulfone Ro 15-1570 did not cause bone alterations. The absence of toxic effects on the bones by Ro 15-1570 was confirmed by X-ray-film examinations, densitometry of the X-rayed femora and tibiae, examination of the thickness of the femoral and tibial compacta in histological slides plus the determination of the femoral ash weight and its main inorganic constituents (calcium, magnesium, sodium, and potassium). The present demonstration that the arotinoid ethylsulfone Ro 15-1570 was devoid of bone toxicity constitutes major progress in the pharmacologic development of retinoids with a better balance between therapeutic and adverse effects.
Subject(s)
Bone and Bones/drug effects , Etretinate/toxicity , Retinoids/toxicity , Tretinoin/toxicity , Animals , Body Weight/drug effects , Bone and Bones/analysis , Etretinate/administration & dosage , Female , Femoral Fractures/chemically induced , Femur/analysis , Femur/drug effects , Male , Rats , Skin/drug effects , Tibia/drug effects , Tibial Fractures/chemically induced , Tretinoin/administration & dosageABSTRACT
Etretinate (Ro 10-9359; Tigason; 4-methoxy-2,3,6-trimethylphenyl analog of retinoic acid, ethyl ester) was evaluated for teratogenic activity in the Syrian golden hamster. Groups of pregnant hamsters were given a single oral dose of 2.8-88 mg/kg etretinate during the early primitive streak stage of gestation. No signs of maternal intoxication were observed in any of the hamsters given the retinoid and maternal body weight changes throughout gestation were not significantly different from those of the vehicle-treated group. Etretinate administration was associated with a dose-dependent increase in the incidence and severity of malformations. The average fetal body weight was significantly less in litters recovered from dams given 44 or 88 mg/kg of etretinate when compared to the average body weight of fetuses recovered from dams given an equivalent volume of the vehicle. The average crown-rump lengths also were significantly shorter in fetuses taken from the dams given 44 or 88 mg/kg etretinate as compared to the control group. The malformations induced by etretinate administration were similar to those noted following an oral dose of all-trans-retinoic acid (Willhite and Shealy, 1984). A comparison of the dose-response curves for induction of terata following treatment with etretinate or all-trans-retinoic acid revealed that etretinate was twice as potent as a teratogen in the hamster as all-trans-retinoic acid. Teratogenic activity of etretinate in the hamster was achieved at doses (mg/kg body wt) used in patients at current clinical therapeutic levels.