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  • 1
    Language: English
    In: Diabetes care, May 2002, Vol.25(5), pp.815-21
    Description: Troglitazone treatment has been associated with idiosyncratic hepatic reaction leading to hepatic failure and death in some patients. This raises questions regarding whether all thiazolidinediones or peroxisomal proliferator-activated receptor-gamma (PPAR-gamma) agonists are hepatotoxic and whether data from clinical trials are adequate to detect a signal of potentially serious drug-related hepatotoxicity. The purpose of this study was to assess whether the idiosyncratic liver toxicity reported with troglitazone is molecule-specific or a thiazolidinedione class effect, based on liver enzyme data collected prospectively during phase 2/3 clinical trials with rosiglitazone, a new, potent, and specific member of the thiazolidinedione class. This is an analysis of liver function in type 2 diabetic patients at baseline and serially in 13 double-blind, 2 open-label active-controlled, and 7 open-label extension studies of rosiglitazone treatment conducted in outpatient centers throughout North America and Europe. The study comprised 〉 6,000 patients aged 30-80 years with type 2 diabetes. Patients underwent baseline liver function studies and were excluded from clinical trials if they had an alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase value 2.5 times greater than the upper limit of the reference range. The main outcome measures were liver enzyme levels, which were assessed at screening, at baseline, and every 4 weeks for the first 3 months of treatment and at 6- to 12-week intervals thereafter. Patients with at least one on-therapy ALT value 〉3 times the upper limit of the reference range were identified, and their case records examined in detail. At baseline, 5.6% of the patients with type 2 diabetes (mean HbA(1c) 8.5-9.0%) had serum ALT values between 1.0 and 2.5 times the upper limit of the reference range. On antidiabetic therapy, most of those patients ( approximately 83%) had a decrease in ALT values, many into the normal range. The percentages of all patients with an on-therapy ALT value 〉3 times the upper limit of the reference range during double-blind and open-label treatment were as follows: rosiglitazone-treated 0.32%, placebo-treated 0.17%, and sulfonylurea-, metformin-, or insulin-treated 0.40%. The respective rates of ALT values 〉3 times the upper limit of the reference range per 100 person-years of exposure were 0.29, 0.59, and 0.64. No evidence of hepatotoxic effects was observed in studies that involved 5,006 patients taking rosiglitazone as monotherapy or combination therapy for 5,508 person-years. This is in keeping with hepatic data from clinical trials of another member of the class, pioglitazone, and in contrast to the clear evidence of hepatotoxic effects observed during the troglitazone clinical trial program. These findings suggest that the idiosyncratic liver toxicity observed with troglitazone is unlikely to be a thiazolidinedione or a PPAR-gamma agonist class effect. Poorly controlled patients with type 2 diabetes may have moderate elevations of serum ALT that will decrease with improved glycemic control during treatment with rosiglitazone or other antihyperglycemic agents.
    Keywords: Thiazolidinediones ; Diabetes Mellitus, Type 2 -- Drug Therapy ; Hypoglycemic Agents -- Therapeutic Use ; Liver Failure -- Chemically Induced ; Metformin -- Adverse Effects ; Thiazoles -- Therapeutic Use
    ISSN: 0149-5992
    E-ISSN: 19355548
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  • 2
    In: Diabetes, 1999, Vol.48(5), p.SA117
    Keywords: Diabetes Research
    ISSN: 0012-1797
    Source: Cengage Learning, Inc.
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  • 3
    Language: English
    In: Pharmacology, Biochemistry and Behavior, 1987, Vol.27(1), pp.7-14
    Description: 5,7-DHT (104 micrograms) was injected into the third brain ventricle of three-day-old rat pups 1 hr after desmethylimipramine pretreatment (20 mg/kg IP). Whole-brain serotonin was depleted by 50%, and there was some retardation of weight gain. Nipple attachment was observed in sucklings and in weaned pups. When 9 days old, attachment in 5-HT depleted pups was delayed and they were less active when undeprived, but not when 8 hr deprived. In comparison with pups raised in litters of 6 or 14, which served to control for reduced body weight, depleted pups' behavior was more similar to the heavier pups, suggesting that the behavioral differences were not due to retarded growth. After weaning at 21 days, depleted pups attached more up to 37 days of age, after which attachment was not reinstated by treatment with methysergide, suggesting that the waning of depletion induced attachment was not due to recovery of serotonergic function. Again, body weight controls showed that the effects were not due to retarded weight gain in the depleted pups. The results confirm the biphasic action of 5-HT antagonism on attachment, i.e., inhibition in the neonate and disinhibition in the weanling. The findings also show that central 5-HT systems are involved in the inhibition of attachment during weaning, but that this involvement is transient, and apparently not crucial.
    Keywords: Attachment ; 5,7-Dihydroxytryptamine ; Ontogeny ; Rat Pups ; Serotonin ; Pharmacy, Therapeutics, & Pharmacology ; Psychology
    ISSN: 0091-3057
    E-ISSN: 1873-5177
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  • 4
    In: Annals of the New York Academy of Sciences, March 1989, Vol.553(1), pp.314-324
    ISSN: 0077-8923
    E-ISSN: 1749-6632
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  • 5
    Language: English
    In: Neuroscience Letters, 1989, Vol.104(1), pp.7-12
    Description: Thyrotropin-releasing hormone-like immunoreactivity (TRH-LI) was localized at the ultrastructural level in the dorsal vagal complex (DVC: dorsal motor nucleus of the vagus (DMV) and the nucleus of the solitary tract (NST)) in rat. TRH-LI was concentrated in large granular vesicles in axons, presynaptic terminals, and non-synaptic axon varicosities. TRH-LI presynaptic terminals established both asymmetric and symmetric synaptic contacts with dendrites. These observations are consistent with recently described direct inhibitory and facilitatory effects of TRH on the electrical activity of neurons in the DVC.
    Keywords: Dorsal Motor Nucleus of the Vagus ; Thyrotropin-Releasing Hormone ; Nucleus Tractus Solitarii ; Electron Microscopy ; Gastric ; Rat ; Medicine ; Anatomy & Physiology
    ISSN: 0304-3940
    E-ISSN: 1872-7972
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  • 6
    Language: English
    In: The American Journal of Cardiology, 2002, Vol.90(9), pp.947-952
    Description: This study evaluated the effects of rosiglitazone therapy on lipids and the efficacy and safety of rosiglitazone in combination with atorvastatin in patients with type 2 diabetes mellitus. Three-hundred thirty-two patients entered an 8-week, open-label, run-in treatment phase with rosiglitazone 8 mg/day, and 243 were randomized to a 16-week, double-blinded period of continued rosiglitazone plus placebo, atorvastatin 10 mg/day, or atorvastatin 20 mg/day. With rosiglitazone alone, a modest increase in low-density lipoprotein (LDL) cholesterol (9%), a shift in LDL phenotype from dense to large buoyant subfractions (52% of patients), and an increase in total high-density lipoprotein (HDL) cholesterol levels (6%), predominantly in HDL(2) levels (13%), occurred from week 0 to week 8. When atorvastatin was added, there was a further increase in HDL(3) (5%) and expected significant reductions (p 〈0.0001) in LDL cholesterol (-39%), apolipoprotein B (-35%), and triglyceride levels (-27%). Glycemic control achieved with rosiglitazone alone was not adversely affected by add-on atorvastatin. The combination was well tolerated compared with placebo. To conclude, in addition to the beneficial effects of rosiglitazone on glycemic control, rosiglitazone and atorvastatin in combination achieved 2 goals: the reduction of LDL cholesterol to 〈100 mg/dl and the removal of small dense LDL in patients with type 2 diabetes mellitus.
    Keywords: Medicine
    ISSN: 0002-9149
    E-ISSN: 1879-1913
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  • 7
    Language: English
    In: Brain Research, 1990, Vol.520(1), pp.291-302
    Description: Systemic administration of the neurotoxin 3-acetylpyridine (3-AP) to rats produced spontaneous episodes of spasmodic movement involving the trunk and limbs including torticollis, contortions of the trunk and rigid extension of the limbs. Because the neurotransmitter serotonin (5-HT) has been implicated in various human involuntary movement disorders, the functional and anatomical integrity of the 5-HT system in rats treated with 3-AP were examined. 5-HT-containing neurons in the brain stem were studied using immunohistochemical labeling with antiserum to 5-HT. Cells in the nucleus raphe obscurus were found to be altered following 3-AP treatment as shown by a decrease in 5-HT immunoreactivity as compared to control rats. No changes in 5-HT immunoreactivity were observed in any other region containing 5-HT cell bodies. Behaviorally, rats treated with 3-AP were 2.5-fold more sensitive to the ability of the 5-HT agonist 8-OH-2-(di- -propylamino)tetralin (8-OH-DPAT; 0.33–3.3 mg/kg) to produce the 5-HT syndrome. Similarly, 3-AP-treated rats were 2-fold more sensitive to the selective 5-HT agonist 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB; 0–1.0 mg/kg) at producing the head shake response. Although these behaviors associated with brain stem 5-HT receptors were potentiated by 3-AP, the hypothermic effect of 8-OH-DPAT which involves ascending mesencephalic 5-HT neurons was unchanged following 3-AP treatment. Treatment with 3-AP did not produce significant alterations of 5-HT or 5-hydroxyindoleacetic acid (5-HIAA) content in any brain region studied. Quantitative autoradiographic analysis of the density of 5-HT receptors labeled with [ H]8-OH-DPAT revealed that these sites were largely unchanged in regions of the brain (frontal cortex, hippocampus and brain stem) and in the spinal cord. Similarly, few changes in the density of 5-HT receptors measured with [ H]ketanserin were observed in various brain regions. These results suggest that neurons from the nucleus raphe obscurus are involved in the elicitation of 5-HT-mediated behavioral resonses by 5-HT and 5-HT receptor agonists that are thought to be mediated through brain stem and spinal cord mechanisms. In addition, because of the close neuroanatomical relationship of the nucleus raphe obscurus with various brain regions known to be involved in motor control, the destruction of this region by 3-AP may contribute to the spasmodic motor behaviors observed following 3-AP treatment.
    Keywords: 3-Acetylpyridine ; Raphe Obscurus ; Serotonin-Mediated Behavior ; Serotonin Syndrome ; Serotonin Immunocytochemistry ; Anatomy & Physiology
    ISSN: 0006-8993
    E-ISSN: 1872-6240
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  • 8
    Language: English
    In: Biological Psychiatry, 1992, Vol.32(5), pp.411-425
    Description: Male rats made hypothyroid by administration of propylthiouracil plus sodium ipodate in drinking water were compared to controls in terms of period of circadian activity and temperature rhythms, amount of gross motor activity, and mean temperature. Animals were studied under entrainment, constant darkness (DD), and constant dim light (LL). There was no difference in the period of the circadian activity rhythm between groups in DD. However, hypothyroid rats showed significant blunting of the period-lengthening response to increasing ambient illumination. As expected, the period of the circadian temperature rhythm increased in controls with increasing ambient illumination. In contrast, the period of the circadian temperature rhythm in hypothyroid animals actually shortened under LL compared to DD. This blunting of the period-lengthening response to increasing ambient illumination of both activity and temperature rhythms in hypothyroid animals could not be explained by differences in activity level or mean temperature between the groups.
    Keywords: Medicine ; Biology ; Chemistry
    ISSN: 0006-3223
    E-ISSN: 1873-2402
    E-ISSN: 18733402
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  • 9
    Language: English
    In: Brain Research, 1981, Vol.217(1), pp.69-77
    Description: We report that the rat olfactory bulb is rich in thyrotropin releasing hormone (TRH) immunoreactivity. TRH content was determined according to the radioimmunoassay method of Bassiri and Utiger . The concentration (mean ± S.E.M., = 10) of TRH in olfactory bulb (60 ± 10pg/mg wet weight) was 23% of the concentration in the hypothalamus, and was at least twice that of other brain regions examined. The 2 olfactory bulbs (mean wet weight 65 mg/2 bulbs) contained 3.9 ± 0.3 ng TRH. The TRH immunoreactivity could be separated into high and low molecular weight forms. The low molecular weight form co-chromatographed with authentic TRH (mol.wt. 362) on gel filtration and thin layer adsorption chromatography and caused the release of thyrotropin from pituitary tissue incubated in vitro. Since the neuronal organization and functions of the olfactory bulb are well described, studies of the localization and metabolism of TRH in this region may help to clarify the role of this tripeptide in the central nervous system.
    Keywords: Thyrotropin Releasing Hormone ; Olfactory Bulb ; Hypothalamus ; Radioimmunoassay ; Anatomy & Physiology
    ISSN: 0006-8993
    E-ISSN: 1872-6240
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  • 10
    Language: English
    In: Psychopharmacology, 1988, Vol.96(3), pp.289-295
    Description: Administration of the selective serotonin (5-HT) uptake inhibitor sertraline produced a dose-dependent reduction of food intake in rats. Doses of sertraline of 10 mg/kg or greater reduced the intake of solid pellets significantly ( P 〈0.01) during the 1st hour of a 4-h feeding test in rats deprived of food and water for 24 h. Food intake during the remaining 3 h and water intake during the feeding test was unaffected by sertraline. Sertraline (2–18 mg/kg IP) also reduced milk consumption in food-deprived rats. Pretreatment with the nonselective 5-HT antagonists metergoline (2 mg/kg IP) or methysergide (3.3 mg/kg IP) blocked sertraline's inhibition of dry food intake, whereas pretreatment with the selective 5-HT 2 receptor antagonist ketanserin (3.3 mg/kg IP) or the peripheral 5-HT 2 antagonist xylamidine (2.5 mg/kg IP) failed to block sertraline's anorexic effect. The feeding-suppressant effect of 10 mg/kg sertraline was prevented following the destruction of central 5-HT neurons by the 5-HT neurotoxic agent, 5,7-dihydroxytryptamine (200 μg ICV). This result is consistent with sertraline's anorexic effect depending on intact 5-HT neurotransmission. Therefore, sertraline appears to reduce feeding by enhancing the action of endogenous serotonin at central synapses mediated by 5-HT 1 rather than 5-HT 2 receptors.
    Keywords: Serotonin ; 5-HT receptor ; Feeding behavior ; Sertraline ; Antidepressant drugs ; Rats
    ISSN: 0033-3158
    E-ISSN: 1432-2072
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