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Understanding and treating the metabolic syndrome

Guven, Safak; Harris, Alan G.
ISSN: 1746-0875
CID: 4192562

Somatostatin Analogs In The Gastrointestinal Tract

Chapter by: Harris, Alan G.; Daly, Adrian F.; Tichomirowa, Maria; Beckers, Albert; Lamberts, Steven W.
in: Handbook of Biologically Active Peptides by
[S.l.] : Elsevier Inc., 2006
pp. 1131-1138
ISBN: 9780123694423
CID: 4192552

The effects of growth hormone (GH) deficiency and GH replacement on cognitive performance in adults: a meta-analysis of the current literature

Falleti, Marina G; Maruff, Paul; Burman, Pia; Harris, Alan
OBJECTIVE:There is growing evidence in the neuropsychological literature that growth hormone (GH) deficiency is associated with cognitive impairment. There is also evidence that this impairment may be ameliorated with GH replacement therapy. The current study assessed the nature and severity of cognitive impairment associated with growth hormone deficiency, as well as effect of GH replacement on cognitive function by conducting a meta-analysis of the published literature to date. METHOD/METHODS:Thirteen studies met the inclusion criteria and these included: five cross-sectional studies investigating GH deficiency; and, eight (eight prospective, two of which also included cross-sectional comparisons) investigating GH replacement. Effect sizes (Cohen's d) falling into six cognitive domains were computed (separately for GH deficiency and GH replacement). RESULTS:For GH deficiency, each of the cognitive domains assessed (besides language) showed moderate to large impairments when compared to matched controls (Effect sizes -0.46 to -1.46). For GH replacement, even though treated patients still performed moderately to largely below that of controls, when compared to their own baselines (as in prospective analyses), moderate improvements were found in cognitive performance, particularly attention and memory. CONCLUSION/CONCLUSIONS:This meta-analysis clearly demonstrates the link between GH and cognitive performance, where poor performance can be ameliorated with GH treatment.
PMID: 16621325
ISSN: 0306-4530
CID: 4192402

Effect of desloratadine therapy on symptom scores and measures of nasal patency in seasonal allergic rhinitis: results of a single-center, placebo-controlled trial

Meltzer, Eli O; Jalowayski, Alfredo A; Vogt, Klaus; Iezzoni, Domenic; Harris, Alan G
BACKGROUND: Desloratadine reduces symptoms and maintains nasal airflow in patients with seasonal allergic rhinitis (SAR) during experimental allergen exposure. OBJECTIVE: To compare the effects of desloratadine and placebo on symptom scores, quality of life (QOL), and nasal airway patency in patients with SAR during the allergy season. METHODS: Adults with symptomatic SAR were randomized in a double-blind manner to receive desloratadine, 5 mg, or placebo for 14 days. Patient-rated SAR symptoms were recorded twice daily (morning and evening). On days 1 and 15, SAR symptoms were scored jointly (investigator and patient), nasal airflow was measured using 4-phase rhinomanometry, and QOL and the overall condition of SAR were rated. Overall treatment response was scored on day 15. Adverse events were recorded. RESULTS: At day 15, total symptom (P = .03) and total nasal symptom (P = .02) scores and patient morning-rated individual nasal symptom scores (except nasal stuffiness) (P < or = .04) decreased significantly from baseline with desloratadine vs placebo. Flow in the descending expiratory nasal airflow phase was significantly greater (P = .046) and the percentage increase in total inspiratory nasal airway resistance was less (P = .03) in the desloratadine group vs the placebo group. The overall condition of SAR was less severe (P = .045), the therapeutic response was greater (P = .004), and the nasal symptom domain of the QOL score was significantly better (P = .03) in the desloratadine group. Adverse event rates were similar in both groups. CONCLUSION: Desloratadine treatment for 14 days improved nasal airflow and resistance as well as symptom and QOL scores in patients with symptomatic SAR during the allergy season.
PMID: 16498861
ISSN: 1081-1206
CID: 1410042

Mometasone and beclomethasone comparison article observations [7]

Chrousos, George P.; Ghaly, Lisa; Iezzoni, Domenic; Shedden, Arthur; Harris, Alan G.
ISSN: 0012-3692
CID: 4192542

Effects of mometasone furoate dry powder inhaler and beclomethasone dipropionate hydrofluoroalkane and chlorofluorocarbon on the hypothalamic-pituitary-adrenal axis in asthmatic subjects

Chrousos, George P; Ghaly, Lisa; Shedden, Arthur; Iezzoni, Domenic G; Harris, Alan G
STUDY OBJECTIVES: Mometasone furoate dry powder inhaler (MF-DPI) [400 mug] is an inhaled corticosteroid (ICS) that is effective in the treatment of asthma. MF-DPI has a low potential for suppression of the hypothalamic-pituitary-adrenal (HPA) axis at its clinical dose. The effect of MF-DPI, 400 microg qd, on the HPA axis was compared to that of beclomethasone dipropionate (BDP) using hydrofluoroalkane (HFA) and chlorofluorocarbon (CFC) propellants via metered-dose inhalers (MDIs) twice daily. DESIGN AND INTERVENTIONS: This randomized, third-party blind, parallel-group study compared the effects of MF-DPI 400 mug one puff qd in the morning (n = 18), HFA-BDP 200 microg two puffs MDI bid (n = 18), and CFC-BDP 400 microg two puffs MDI bid (n = 17) for 14 days on the area under the 24-h serum cortisol concentrations curve (AUC(0-24)) and on total 24-h urinary free cortisol excretion in mild asthmatic subjects. Effects on morning/evening peak expiratory flow (PEF) and on inhaled albuterol use were also assessed. Adverse events that occurred during or > or = 30 days after the study were recorded. RESULTS: The mean decrease from baseline in the serum cortisol concentrations AUC(0-24) in the MF-DPI group was significantly less than in either the HFA-BDP (p = 0.024) or the CFC-BDP (p = 0.011) groups. Decreases in serum cortisol concentrations AUC(0-24) in the two BDP groups did not differ from one another. The MF-DPI group trended toward higher morning and evening PEF than either BDP group. Treatment-associated adverse events were reported by seven subjects in the MF-DPI group, vs one subject in the HFA-BDP and three subjects in the CFC-BDP groups; these were mild, and no subject discontinued treatment due to an adverse event. CONCLUSIONS: Fourteen days of treatment with MF-DPI 400 microg qd was associated with a significantly lesser decrease in the serum cortisol concentrations AUC(0-24) compared with HFA-BDP 200 microg MDI or CFC-BDP 400 microg MDI bid.
PMID: 16002918
ISSN: 0012-3692
CID: 1410052

Intramuscular administration of ACTH1-24 vs. 24-hour blood sampling in the assessment of adrenocortical function

Alesci, Salvatore; Ilias, Ioannis; Souvatzoglou, Emmanuil; Harris, Alan G; Gold, Philip W; Ayala, Alejandro R; Chrousos, George P
The standard intravenous short Synacthen test (SSST) has long been accepted as one of the most reliable diagnostic tests of adrenocortical insufficiency. Intramuscular (i.m.) administration of ACTH obviates the need of venous cannulation and can be used as an alternative to the intravenous test. Nevertheless, reports of correlation between cortisol response to i.m. ACTH1-24 and 24-hr average cortisol concentration are scarce. We studied this relation in 64 nonobese healthy men. Blood samples for serial cortisol measurements were collected hourly over 24 hrs. The following day, blood samples were collected at baseline and at 30 and 60 min after intramuscular (i.m.) administration of 250 microg of ACTH1-24. All healthy men reached 24-hr serum cortisol peak values (Cmax) between 0600 h and 1000 h. Following i.m. ACTH1-24, cortisol levels significantly increased at both 30 (C30ACTH) and 60 (C60ACTH) minutes, when compared to baseline values. C30ACTH and C60ACTH significantly correlated with Cmax and with the 24-hr time-integrated cortisol concentration (AUC0-24). Morning mean cortisol was calculated as the average of serum concentrations measured between 0600 h and 1000 h (C(av)6-10) and correlated very well with AUC0-24. In conclusion, we confirmed that i.m. administration of ACTH1-24, followed by a single blood sampling at 60 min for cortisol measurement represents a valid, convenient and cost- effective screening test of adrenal function.
PMID: 16613811
ISSN: 1109-3099
CID: 1410062

Desloratadine prevents compound 48/80-induced mast cell degranulation: visualization using a vital fluorescent dye technique

Wang, Y H; Tache, Y; Harris, A G; Kreutner, W; Daly, A F; Wei, J Y
BACKGROUND: Desloratadine is a selective H1-antihistamine used in the treatment of allergic rhinitis and chronic idiopathic urticaria. Desloratadine inhibits the release of allergic inflammatory mediators in vitro. We studied the impact of desloratadine on mast cell degranulation due to activation and re-activation by the secretagogue, compound 48/80. METHODS: Rat peritoneal eluate containing 5-6% mast cells were activated by a low concentration of compound 48/80 in a medium containing the vital fluorescent dye, Sulforhodamine-B (SFRM-B, 200 microg/ml), which is engulfed by activated mast cells. The fluorescent image of activated mast cells was captured digitally and the total fluorescent area was analyzed when desloratadine was applied before or after compound 48/80. RESULTS: Mast cells were not activated by desloratadine (10(-4) M), SFRM-B (200 microg/ml), or diluent alone. A low concentration of compound 48/80 (0.125 microg/ml) induced fluorescence, while mast cells lost fluorescent images due to further degranulation on re-exposure to compound 48/80. Desloratadine (10(-8)-10(-4) M), inhibited compound 48/80-induced mast cell degranulation in a concentration-dependent manner. Desloratadine also reduced the loss of fluorescent images due to re-exposure to compound 48/80. CONCLUSIONS: Desloratadine may have a mast cell stabilizing effect at low concentrations in response to repeated mast cell activation in vitro.
PMID: 15575942
ISSN: 0105-4538
CID: 1410122

Cytokine dysregulation, inflammation and well-being

Elenkov, Ilia J; Iezzoni, Domenic G; Daly, Adrian; Harris, Alan G; Chrousos, George P
Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute-phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1 versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic 'overshooting' with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor-alpha and C-reactive protein production and through activation of the corticotropin-releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases.
PMID: 16166805
ISSN: 1021-7401
CID: 1410072

Desloratadine inhibits constitutive and histamine-stimulated nuclear factor-kappaB activity consistent with inverse agonism at the histamine H1 Receptor

Wu, Ren-Long; Anthes, John C; Kreutner, William; Harris, Alan G; West, Robert E Jr
BACKGROUND: The human histamine H1 receptor is constitutively active and exhibits basal activation of nuclear factor-kappaB (NF-kappaB), an important modulator of allergic inflammation. Certain H1 antihistamines have recently been shown to inhibit basal NF-kappaB activity by stabilizing the H1 receptor in an inactive state, a phenomenon called 'inverse agonism'. METHODS: We evaluated the effect of the new H1 antihistamine, desloratadine, on basal and histamine-stimulated NF-kappaB activity and compared it with the activities of other H1 antihistamines. RESULTS: Transiently transfected COS-7 cells co-expressing NF-kappaB-luciferase and the H1 receptor exhibited constitutive NF-kappaB activity. H1 antihistamines reduced basal NF-kappaB activity (rank order of potency: desloratadine > pyrilamine > cetirizine > loratadine > fexofenadine). Histamine stimulated basal NF-kappaB activity 8-fold, which was blocked by H1 antihistamines (rank order of potency: desloratadine > cetirizine > pyrilamine > loratadine > fexofenadine). Neither histamine nor antihistamines had any effect on NF-kappaB activity in the absence of the H1 receptor. CONCLUSIONS: Desloratadine, acting through the histamine H1 receptor, inhibited basal NF-kappaB activity and can thus be classified as an inverse agonist. Inhibition of basal and histamine-stimulated NF-kappaB activity may help to explain previously reported inhibitory effects of desloratadine on allergic inflammatory mediators.
PMID: 15564772
ISSN: 1018-2438
CID: 1410082