tretinoin and Weight-Gain

The introduction of treatment with tretinoin (all-trans retinoic acid) and its combination with antineoplastic therapy has improved the outcome of acute promyelocytic leukaemia (APL). Retinoic acid syndrome is the major adverse effect of tretinoin and it occurs in about 25% of treated APL patients in the absence of prophylactic measures and is often fatal. Generally, the retinoic acid syndrome is associated with increasing leucocyte counts and is probably caused by the release of several cytokines by maturing blast cells. The retinoic acid syndrome gives a clinical picture of bodyweight gain, respiratory distress, serous effusions and cardiac and renal failure. Adequate prophylaxis, based on the addition to tretinoin of dexamethasone and also, according to most authors, antineoplastic therapy (in case of rapidly increasing leucocyte counts) has decreased the incidence of retinoic acid syndrome to about 15%. Most importantly, these measures have reduced its mortality to about 1% of all treated patients.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Clinical Trials as Topic; Cytokines; Dexamethasone; Heart Failure; Humans; Infant, Newborn; Leukemia, Promyelocytic, Acute; Leukocyte Count; Renal Insufficiency; Respiratory Distress Syndrome, Newborn; Syndrome; Tretinoin; Weight Gain

We examined the incidence, clinical course, and outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) who developed the retinoic acid syndrome (RAS) treated on the Intergroup Protocol 0129, which prospectively evaluated the role of alltrans retinoic acid (ATRA) alone during induction and as maintenance therapy. Forty-four of 167 (26%) patients receiving ATRA for induction developed the syndrome at a median of 11 days of ATRA (range, 2-47). The median white blood cell (WBC) count was 1,450/microL at diagnosis and was 31,000/microL (range, 6,800-72,000/microL) at the time the syndrome developed. ATRA was discontinued in 36 of the 44 patients (82%) and continued in 8 patients (18%), with subsequent resolution of the syndrome in 7 of the 8. ATRA was resumed in 19 of the 36 patients (53%) in whom ATRA was stopped and not in 17 (47%). The syndrome recurred in 3 of those 19 patients, with 1 death attributable to resumption of the drug. Ten of these 36 patients received chemotherapy without further ATRA, and 8 achieved complete remission (CR). Among 7 patients in whom ATRA was not restarted and were not treated with chemotherapy, 5 achieved CR and 2 died. Two deaths were definitely attributable to the syndrome. No patient receiving ATRA as maintenance developed the syndrome. (Blood. 2000;95:90-95)

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Dexamethasone; Female; Fever; Glucocorticoids; Humans; Incidence; Infant; Leukemia, Promyelocytic, Acute; Lung; Male; Middle Aged; Pericardial Effusion; Pleural Effusion; Remission Induction; Respiratory Distress Syndrome; Syndrome; Tretinoin; Weight Gain

This study was conducted to compare the results of treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid alone (ATRA) or a combination therapy of ATRA followed by chemotherapy. Forty-three patients treated between February 1992 and February 1996 were included in this study. Eighteen patients were treated with ATRA alone and 25 patients were treated with ATRA followed by chemotherapy. The cytogenetic analysis was done in 41 patients at presentation, following treatment, and at follow-up. A complete response (CR) was achieved in 13 (72%) patients on ATRA and 19 (76%) on ATRA followed by chemotherapy. Eleven of 13 patients with response to ATRA alone relapsed with median survival of eight months (range, 1 to 28). One patient died of hepatitis in CR and one patient is alive 2 years after diagnosis. In the combination therapy arm, 10 patients are in CR with a median follow-up of 22 months (range, 6 to 56 months). After achieving a CR, four patients died due to infections during chemotherapy therapy, and only 5 of 19 patients have relapsed. Major cytogenetic response was seen in 8 of the 10 patients in whom cytogenetic data was available after treatment with ATRA at the time of remission. Similarly, 13 of 15 for whom data was available showed a major cytogenetic response after treatment with ATRA plus chemotherapy. Prior to relapse, 80% of the patients had an increase in the percentage of t(15;17) cells in the marrow. Patients with a complete hematological response but no cytogenetic response relapsed within six months. Ten patients died prior to response evaluation. Two patients who received ATRA died of retinoic acid syndrome, one of pneumonia, and one of intracranial hemorrhage. Of the six patients on ATRA and chemotherapy, four died of retinoic acid syndrome (RAS), one of intracranial hemorrhage, and one of left ventricular failure. Only one patient is alive at 24 months following treatment with ATRA alone. The relapse-free survival is 42% at four years for patients treated with ATRA followed by chemotherapy. This trial is a historical comparison of ATRA alone and ATRA with subsequent combination chemotherapy. Nonetheless, the trial shows a significant improvement in the event free survival of patients receiving chemotherapy as consolidation following ATRA.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Child; Cytarabine; Daunorubicin; Female; Fever; Humans; Leukemia, Promyelocytic, Acute; Lung; Male; Middle Aged; Prospective Studies; Recurrence; Remission Induction; Survival Rate; Tretinoin; Weight Gain

Maternal obesity may compromise the micronutrient status of the offspring. Vitamin A (VA) is an essential micronutrient during neonatal development. Its active metabolite, retinoic acid (RA), is a key regulator of VA homeostasis, which also regulates adipose tissue (AT) development in obese adults. However, its role on VA status and AT metabolism in neonates was unknown and it was determined in the present study. Pregnant Sprague-Dawley rats were randomised to a normal fat diet (NFD) or a high fat diet (HFD). From postnatal day 5 (P5) to P20, half of the HFD pups received oral RA every 3 d (HFDRA group). NFD pups and the remaining HFD pups (HFD group) received placebo. Six hours after dosing on P8, P14 and P20,

Topics: Adipose Tissue; Animals; Animals, Newborn; Diet, High-Fat; Female; Humans; Micronutrients; Obesity; Obesity, Maternal; Pregnancy; Rats; Rats, Sprague-Dawley; Tretinoin; Vitamin A; Weight Gain

Knowledge of the regulation of testicular retinoic acid synthesis is crucial for understanding its role in spermatogenesis. Bisdichloroacetyldiamines strongly inhibit spermatogenesis. We reported previously that one of these compounds, WIN 18,446, potently inhibited spermatogenesis in rabbits by inhibiting retinoic acid synthesis. To understand how WIN 18,446 inhibits retinoic acid synthesis, we characterized its effects on human retinal dehydrogenase ALDH1A2 in vitro as well as its effects on retinoid metabolism in vivo using mice. WIN 18,446 strongly and irreversibly inhibited ALDH1A2 in vitro. In vivo, WIN 18,446 treatment completely abolished spermatogenesis after 4 weeks of treatment and modestly reduced adiposity in mice fed a chow diet. Effects of WIN 18,446 on retinoid concentrations were tissue-dependent. Although lung and liver retinyl ester concentrations were lower in WIN 18,446-treated animals, adipose retinyl ester levels were increased following the treatment. Interestingly, animals treated with WIN 18,446 had significantly higher circulating retinol concentrations compared with control mice. The effect on spermatogenesis by WIN 18,446 was not prevented by simultaneous treatment with retinoic acid, whereas effects on other tissues were partially or completely reversed. Cessation of WIN 18,446 treatment for 4 weeks reversed most retinoid-related phenotypes except for inhibition of spermatogenesis. Our data suggest that WIN 18,446 may be a useful model of systemic acquired retinoic acid deficiency. Given the effects observed in our study, inhibition of retinoic acid biosynthesis may have relevance for the treatment of obesity and in the development of novel male contraceptives.

Topics: Adipose Tissue; Aldehyde Dehydrogenase 1 Family; Animals; Biocatalysis; Diamines; Electrophoresis, Polyacrylamide Gel; Esters; Humans; Liver; Lung; Male; Mice; Mice, Inbred C57BL; Retinal Dehydrogenase; Retinoids; Spermatocytes; Spermatogenesis; Testis; Tretinoin; Vitamin A; Weight Gain

Topics: Aged; Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Lung Diseases; Lymphohistiocytosis, Hemophagocytic; Male; Syndrome; Tretinoin; Weight Gain

Research has indicated that excessive vitamin A can have deleterious impacts on bone. Retinoic acid (RA), the most active metabolite of vitamin A, has been tested in clinical trials for treatment of lung cancer and emphysema. These trials are not measuring Bone Mineral Content (BMC) or Bone Mineral Density (BMD). In this study, we used an animal model to determine potential deleterious effects of all-trans RA on bone mass when used as a means to protect against or treat cigarette smoke-induced lung injuries, and also to evaluate BMC as a potential early indicator of osteoporosis risk. Twenty-four male weanling rats were fed either a control diet or a RA-supplemented diet. Half of each group was exposed to 40 cigarettes per day, 5 days per week, for 4 weeks. BMC and BMD were measured at weeks 2 and 4. RA supplementation in all groups significantly decreased (p < 0.05) only BMC at week 2 and both BMC and BMD (both p < 0.05) at week 4. The same results were observed when BMC was expressed relative to body weight. These data suggest that caution should be used when RA is used to treat smoke-related lung injuries.

Topics: Absorptiometry, Photon; Animals; Atmosphere Exposure Chambers; Biomarkers; Bone Density; Bone Resorption; Dietary Supplements; Early Diagnosis; Lung Diseases; Male; Osteoporosis; Pulmonary Emphysema; Random Allocation; Rats; Rats, Sprague-Dawley; Smoking; Time Factors; Tretinoin; Weaning; Weight Gain

We previously described that the intake of pharmacological doses of beta-carotene (BC) resulted in higher body weight gain in the ferret (Mustela putorius furo), an animal model that resembles human subjects in terms of intestinal BC absorption and metabolism. These results were some way unexpected considering the condition of BC as a vitamin A precursor and the previous data in rodents showing these compounds as thermogenic activators. Here, we aimed to characterise in the ferret whether the mentioned changes in body weight could be explained by changes in adipose tissue thermogenic capacity. We studied the effects of 6-month supplementation with BC (0.8 and 3.2 mg/kg per d) on adipose tissue morphology and uncoupling protein-1 (UCP1) content. BC supplementation resulted in higher body weight (the high dose), induced depot- and dose-dependent hypertrophy of white adipocytes, decreased the amount of brown-like multilocular adipocytes in the retroperitoneal depot and decreased UCP1 content in different fat depots. To ascertain whether BC effects could be mediated by retinoic acid (RA), 1 week supplementation with RA (0.25 and 25 mg/kg per d) was also studied. RA treatment resulted in a slight decrease in adiposity, decreased cell lipid accumulation and increased UCP1 content, suggesting that the effects of BC on thermogenic capacity are not through RA. In conclusion, RA, but not BC, may have in the ferret comparable effects with those described in rodents, whereas differences concerning BC and RA treatments may be attributable to the different BC metabolism in the present animal model with a lower conversion of BC to RA compared with rodents.

Topics: Adipose Tissue; Adiposity; Animals; beta Carotene; Dietary Supplements; Dose-Response Relationship, Drug; Female; Ferrets; Ion Channels; Mitochondrial Proteins; Models, Animal; Thermogenesis; Tretinoin; Uncoupling Protein 1; Weight Gain

To analyse the impact of vitamin A supplementation of both a normal fat (NF) diet and a high fat (HF) diet and of acute retinoic acid (RA)-treatment on the expression of uncoupling protein 3 (UCP3) in mice.. C57BL/6J mice were fed for 18 weeks a NF or a HF diet (10 and 45 energy% as fat, respectively), both with the normal vitamin A content or an excess vitamin A (8 mg and 320 mg retinyl palmitate/kg diet, respectively). Body weight and energy intake were recorded periodically. UCP3 mRNA and UCP3 protein levels in skeletal muscle (soleus/gastrocnemius) were analysed, as well as UCP1, UCP2 and UCP3 mRNA levels in interscapular brown adipose tissue (BAT), and UCP2 mRNA, UCP2 protein and leptin mRNA levels in white adipose tissue (WAT) depots. The effect of acute RA-treatment (100 mg/kg/day, 4 days) on UCP3 mRNA levels in skeletal muscle and BAT of NMRI mice was also assessed.. Vitamin A supplementation of a NF diet led to increased levels of UCP3 mRNA and UCP3 protein in muscle, UCP1 mRNA in BAT, and UCP2 mRNA in inguinal WAT, but had no impact on body weight or adiposity of B6 mice. HF diet promoted obesity and increased levels of UCP3 mRNA and UCP3 protein in skeletal muscle, and of the mRNAs for all three UCPs in BAT. Supplementing the HF diet with vitamin A had little effect on the final obesity reached and did not lead to further increases of muscle UCP3 mRNA nor BAT UCP1 mRNA over the levels achieved with the non-supplemented HF diet. Adipose leptin mRNA levels were down regulated after vitamin A supplementation, independently of the fat content of the diet. Up-regulation of muscle, but not BAT, UCP3 mRNA levels was also found after acute RA-treatment in NMRI mice.. The results provide evidence of a stimulatory effect of retinoids on muscle UCP3 expression in vivo, and a differential retinoid-regulation of the UCP3 gene in muscle and BAT.

Topics: Adipose Tissue; Animals; Blotting, Western; Carrier Proteins; Dietary Fats; Dietary Supplements; Energy Intake; Ion Channels; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Muscle, Skeletal; RNA, Messenger; Tretinoin; Uncoupling Protein 3; Up-Regulation; Vitamin A; Weight Gain

Thioretinamide was conjugated to coenzyme B12 to produce thioretinaco. Thioretinamide, thioretinaco, and coenzyme B12 were injected weekly into Rattus rattus that were also given atherogenic doses of homocysteine thiolactone. The presence or absence of lesions in aorta-intercostal artery junctions was examined. Control rats injected with homocysteine thiolactone (CON-Hcy) had 56.6 +/- 5.8% lesions when compared to 34.8 +/- 3.4% in control rats injected with saline (CON-Sal). Rats that received homocysteine thiolactone injection with thioretinamide (NHTR-Hcy), thioretinaco ((NHTR)2B12-Hcy), and coenzyme B12 (B12-Hcy) had 30.1 +/- 4.2%, 27.5 +/- 3.5%, and 22.8 +/- 3.0% lesions, respectively. These lesion rates were not different from those of rats receiving thioretinamide (NHTR-Sal), thioretinaco ((NHTR)2B12-Sal), and coenzyme B12 (B12-Sal) which were 31.3 +/- 1.8%, 29.8 +/- 3.9%, and 32.0 +/- 4.6%, respectively. In this study the percentage of intercostal artery lesions in rats receiving thioretinamide and homocysteine (NHTR-Hcy), coenzyme B12 and homocysteine (B12-Hcy), and thioretinaco and homocysteine ((NHTR)2/B12-Hcy) were significantly lower, 53.2%, 48.6%, and 40.3% respectively, compared to than that of the control group receiving homocysteine (CON-Hcy). Thioretinaco, thioretinamide, and coenzyme B12 provided protective effects against the atherogen homocysteine thiolactone. A new method for the synthesis of the N-substituted derivative of homocysteine thiolactone, thioretinamide, was also reported.

Topics: Animals; Aorta, Thoracic; Arterial Occlusive Diseases; Arteries; Arteriosclerosis; Cobamides; Female; Food; Homocysteine; Magnetic Resonance Spectroscopy; Mass Spectrometry; Propylene Glycol; Rats; Tissue Fixation; Tretinoin; Vitamin B 12; Weight Gain

The treatment of acute promyelocytic leukemia with all-trans-retinoic acid (ATRA) sometimes results in a syndrome characterized by fever, respiratory distress, weight gain, pleural and pericardial effusion, and pulmonary infiltrates. We report the radiologic features of ATRA syndrome.. During the past 5 years, 69 patients with acute promyelocytic leukemia were treated with ATRA. Of this group, 15 patients developed ATRA syndrome. Serial chest radiographs of the 15 patients with ATRA syndrome were evaluated retrospectively for the presence of pleural effusion, pulmonary nodules, consolidation, ground-glass opacity, septal lines, increased pulmonary blood volume, peribronchial cuffing, and air bronchogram. Also, we measured the cardiothoracic ratio and the vascular pedicle width.. Chest radiographs showed increased cardiothoracic ratio in 13 of the 15 patients, increased vascular pedicle width in 13, increased pulmonary blood volume in 13, septal lines in nine, peribronchial cuffing in nine, ground-glass opacity in nine, consolidation in seven, and nodules in seven. Pleural effusion was noted in 11 of the 15 patients, and air bronchogram was noted in five of the 15 patients. Pulmonary hemorrhage developed in three patients who were being treated with ATRA; they showed bilateral, diffuse, poorly defined nodules and ground-glass opacity on radiography.. Most patients with ATRA syndrome have abnormal findings on chest radiographs, and the abnormalities are similar to those of pulmonary edema.

Topics: Adult; Antineoplastic Agents; Female; Fever; Humans; Lung Diseases; Male; Middle Aged; Pericardial Effusion; Pleural Effusion; Radiography; Syndrome; Tretinoin; Weight Gain

We report a case of Sweet's syndrome associated with retinoic acid syndrome in a patient with acute promyelocytic leukemia treated with all- trans retinoic acid (ATRA). Sweet's syndrome appeared on day 6 of ATRA therapy for promyelocytic leukemia. It was associated with a mild retinoic acid syndrome, an inflammatory syndrome occurring in 25% of patients treated with ATRA and characterized by features of capillary leakage with systemic inflammatory signs. The ATRA therapy was discontinued for 11 days and treatment with corticosteroids improved the systemic and cutaneous signs. Only 11 cases of Sweet's syndrome associated with ATRA have been previously reported in the literature, involving only the skin in eight cases, the skin and muscles in two cases, and the lung, kidney, fascia, and muscles in one case. Sweet's syndrome was followed by retinoic acid syndrome in one of these cases. The previously reported cases are reviewed, and the mechanisms of Sweet's and retinoic acid syndromes and the link between them are discussed.

Topics: Antineoplastic Agents; Fever; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Sweet Syndrome; Syndrome; Tretinoin; Weight Gain

After the subcutaneous injection of retinoyl beta-glucuronide (RAG), both RAG and retinoic acid (RA), formed by the hydrolysis of RAG in vivo, achieved peak plasma concentrations within 1-2 h. Thereafter, RA was rapidly cleared from the plasma whereas RAG was eliminated much more slowly. No significant changes were noted in the peak (2 h) plasma levels of RAG for treatment periods up to 56 days (one injection of RAG/day), in the clearance rate of RAG from plasma, or in plasma retinol concentrations. Similarly, no consistent decrease in plasma levels of the RA hydrolysis product was observed. Mice undergoing these long-term chronic treatments with RAG did not show any clinical manifestations of retinoid toxicity. Taken together, our findings that chronic dosing with RAG produces sustained levels of both the parent compound and the RA hydrolysis product, combined with the apparent low toxicity of RAG, suggest that RAG could be a safe and useful alternative to some retinoids which are presently being utilized in the clinic.

Topics: Animals; Female; Humans; Liver; Mice; Mice, Inbred ICR; Safety; Time Factors; Tretinoin; Tumor Cells, Cultured; Vitamin A; Weight Gain

All-trans-retinoic acid (ATRA) can induce a clinical remission in patients with acute promyelocytic leukemia. An adverse condition called "retinoic acid syndrome" limits this therapy. It is characterized by fever and respiratory distress, along with weight gain, pleural or pericardial effusions, peripheral edema, thromboembolic events, and intermittent hypotension. The lung disease has been previously ascribed to an infiltration of leukemic or maturing myeloid cells into lung parenchyma, which is sometimes associated with pleural effusions and diffuse alveolar hemorrhage. We report a case of retinoic acid syndrome in an 18-yr-old woman who developed diffuse alveolar hemorrhage while being treated with ATRA for acute promyelocytic leukemia. An open lung biopsy revealed pulmonary capillaritis.

Topics: Adolescent; Antineoplastic Agents; Capillaries; Edema; Female; Fever; Hemoptysis; Humans; Hypotension; Leukemia, Promyelocytic, Acute; Lung; Pericardial Effusion; Pleural Effusion; Pulmonary Alveoli; Respiratory Insufficiency; Syndrome; Thromboembolism; Tretinoin; Vasculitis; Weight Gain

Topics: Adrenal Cortex Hormones; Adult; Antineoplastic Combined Chemotherapy Protocols; Bronchoalveolar Lavage Fluid; Dyspnea; Fever; Humans; Leukemia, Promyelocytic, Acute; Male; Syndrome; Tretinoin; Weight Gain

Prenatal cocaine exposure is associated with disrupted state control and lowered activity levels. Prenatal retinoic acid excess also influences activity levels in laboratory rats. Activity level is usually monitored during a brief period in young offspring. The effects of these drugs on pup activity levels throughout the day is unknown. There is also little information on the long-lasting effects of these teratogens in adult animals. We compared the daily activity of rats which were prenatally exposed to cocaine or retinoic acid (RA). Appropriate control groups were also used. The offspring were evaluated for activity levels in a neophobic situation and for a 22-h period in same-sex groups of 3 littermates. As both pups and adults, the cocaine groups were hypoactive while the RA group was hyperactive when first placed into the testing cage (neophobic situation). Similarly, during the remainder of the 22-h testing period, the pup and adult cocaine animals exhibited reduced activity levels while the RA animals exhibited elevated activity levels. Thus, prenatal cocaine and retinoic acid exposures affected offspring activity levels differently, both drugs have long-lasting neurobehavioral effects that persist into adulthood, and effects are influenced by time-of-day. Strain-dependent differences and mechanisms of action are discussed.

Topics: Activity Cycles; Animals; Cocaine; Drinking; Eating; Female; Narcotics; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Tretinoin; Weight Gain

The embryotoxic and teratogenic potential of all-trans retinoic acid was assessed following exposure prior to and during early organogenesis in the cynomolgus monkey (Macaca fascicularis). Sixteen pregnant females were orally administered all-trans retinoic acid (Tretinoin, Hoffmann-La Roche) once daily from GD 10-20 and twice daily from GD 21-24 at three different dosages, 5 (n = 9), 10 (n = 6) and 20 mg/kg (n = 1). Adverse clinical signs resembling hypervitaminosis A were observed in one animal at 5 mg/kg, in three animals at 10 mg/kg, and in the animal treated with 20 mg/kg all-trans retinoic acid. Maternal weight loss was observed in the 10- and 20-mg/kg groups. A dose-dependent increase in embryolethality was observed, with 22% (2/9), 50% (3/6), and 100% (1/1) occurring at 5, 10, and 20 mg/kg, respectively. The majority of embryonic deaths occurred between GD 16 and 20; the incidence of these early losses was higher than in historical and concurrent controls. No malformations, but a single growth-retarded fetus, was observed in the 5-mg/kg group. Craniofacial malformations, consisting of external ear defects, mandibular hypoplasia, cleft palate, and temporal bone abnormalities, were seen in three viable fetuses in the 10-mg/kg group. Skeletal variations were common to the majority (70%, 7/10) of viable fetuses in both dose groups and were increased relative to historical controls (32%, 25/77). Unlike previous studies with 13-cis-retinoic acid during the pre- and early organogenic stages of development (Hummler et al., Teratology 42:263-272, 1990), no thymic hypo- or aplasia or heart anomalies were observed, which may be attributable to the slightly longer 13-cis retinoic acid treatment period, i.e., GD 10-27. However, external ear and temporal bone defects were common to both all-trans and 13-cis retinoic acid. The similarity observed in the malformation syndrome induced by both all-trans and 13-cis retinoic acid in the cynomolgus monkey and 13-cis retinoic acid embryopathy in humans supports this macaque species as a model for further developmental toxicity studies of vitamin A-related compounds.

Topics: Abnormalities, Drug-Induced; Animals; Embryo, Mammalian; Female; Fetal Death; Macaca fascicularis; Male; Pregnancy; Teratogens; Tretinoin; Weight Gain