RESUMEN
AIMS: To test the hypothesis that glycaemic control achieved when switching sitagliptin to exenatide twice daily plus metformin is non-inferior to adding exenatide twice daily to sitagliptin and metformin. METHODS: Patients with Type 2 diabetes inadequately controlled with sitagliptin plus metformin were randomly assigned to 20 weeks of treatment with twice-daily exenatide plus placebo and metformin (SWITCH, n = 127) or twice-daily exenatide plus sitagliptin and metformin (ADD, n = 128). RESULTS: Non-inferiority (0.4% margin) of SWITCH to ADD treatment, measured by change in HbA(1c) from baseline to week 20, was not shown {between-treatment difference in least-squares mean [95% CI 3 mmol/mol (0.30%)] [0.8-5.8 (0.07-0.53)]}. A greater reduction (P = 0.012) in HbA(1c) [least-squares mean (se)] was experienced by patients in the ADD group {-7 mmol/mol [-0.68%] [0.9 (0.08)]}, compared with those in the SWITCH group {-4 mmol/mol [-0.38%] [1.0 (0.09)]} and a greater proportion (P = 0.027) of patients in the ADD group (41.7%) reached < 7.0% (< 53 mmol/mol) HbA(1c) target, compared with those in the SWITCH group (26.6%) by week 20. Patients in the ADD group experienced greater fasting serum glucose (P = 0.038) and daily mean postprandial self-monitored blood glucose (P = 0.048) reductions, compared with patients in the SWITCH group, by week 20. Patients in both groups experienced a lower incidence of nausea and vomiting compared with previous exenatide studies. CONCLUSIONS: Non-inferiority of SWITCH to ADD treatment was not supported by the results of this study. In patients with Type 2 diabetes inadequately controlled with sitagliptin plus metformin, adding exenatide provided better glycaemic control than switching to exenatide. These results are consistent with the clinical approach that adding is better than switching to another oral anti-hyperglycaemic medication.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Péptidos/administración & dosificación , Pirazinas/administración & dosificación , Triazoles/administración & dosificación , Ponzoñas/administración & dosificación , Adolescente , Adulto , Anciano , Argentina/epidemiología , Australia/epidemiología , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Método Doble Ciego , Esquema de Medicación , Exenatida , Femenino , Alemania/epidemiología , Hemoglobina Glucada/metabolismo , Grecia/epidemiología , Humanos , Hipoglucemia/sangre , Hipoglucemia/epidemiología , Hipoglucemiantes/farmacología , India/epidemiología , Masculino , Metformina/farmacología , México/epidemiología , Persona de Mediana Edad , Péptidos/farmacología , Pirazinas/farmacología , República de Corea/epidemiología , Fosfato de Sitagliptina , Resultado del Tratamiento , Triazoles/farmacología , Ponzoñas/farmacologíaRESUMEN
BACKGROUND: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) share the same transmission routes. About 30% of HIV-positive patients are co-infected with HCV. Of the various HCV-related extrahepatic events, those involving the skin may be the first sign of infection. AIM: To specify the skin presentations in patients co-infected with HIV and HCV (co-infected patients; CP) and compare them with those found in patients with HCV mono-infection (mono-infected patients; MP). METHODS: This was a cross-sectional study, in which the studied population consisted of MP and CP from a tertiary hospital in the South of Brazil, who underwent complete skin examination and laboratory tests. RESULTS: In total, 201 patients were assessed, of whom 108 were CP, and 93 were MP. Pruritus tended to be more common in MP. MP also had significantly more dermatological conditions (mean of 5.2) than CP (mean of 4.5). In total, 104 different skin diseases were identified. There was a higher prevalence of infectious diseases and pigmentation disorders, such as verruca vulgaris and facial melasma, in CP, whereas trunk and facial telangiectasias, palmar erythema, and varicose veins were more common in MP. CONCLUSION: We found a high prevalence of skin conditions both in MP and in CP; however, the patterns of the dermatological conditions were different. CP were found to have significantly fewer skin lesions than MP, but had a higher prevalence of infectious and pigmentation disorders. By contrast, vascular conditions were more common in MP.
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Coinfección/complicaciones , Infecciones por VIH/complicaciones , Hepatitis C/complicaciones , Enfermedades de la Piel/etiología , Adulto , Anciano , Brasil/epidemiología , Coinfección/virología , Estudios Transversales , Femenino , Infecciones por VIH/virología , Hepatitis C/virología , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Enfermedades de la Piel/epidemiología , Enfermedades de la Piel/patologíaRESUMEN
It has been shown that hexarelin stimulates ACTH and cortisol secretion in patients with Cushing's disease. The ACTH release induced by this peptide is 7-fold greater than that obtained by hCRH. The mechanism of action of hexarelin on the hypothalamic-pituitary-adrenal axis has not been fully elucidated. Although controversial, there is evidence that it might be mediated by arginine vasopressin (AVP). The aim of this study was to evaluate the ACTH and cortisol releasing effects of GHRP-6 in patients with Cushing's disease and to compare them with those obtained with DDAVP administration. We studied 10 patients with Cushing's disease (8 female, 2 male; age: 36.7 +/- 4.2 yr), 9 with microadenomas, who were submitted to both GHRP-6 (2 microg/kg iv) and DDAVP (10 micro g i.v.) in bolus administration on 2 separate occasions. ACTH was measured by immunochemiluminometric assay and cortisol by radioimmunoassay. The sensitivities of the assays are 0.2 pmol/l for ACTH, and 11 nmol/l for cortisol. GHRP-6 was able to increase significantly both ACTH (pmol/l, mean +/- SE; basal: 15.5 +/- 1.7 vs peak: 45.1 +/- 9.3) and cortisol values (nmol/l, basal: 583.0 +/- 90.8 vs peak: 1013.4 +/- 194.6). ACTH AUC (pmol/l min(-1)) and cortisol AUC (nmol/l min(-1)) values were 1235.4 and 20577.2, respectively. After DDAVP administration there was a significant increase in ACTH (basal: 13.0 +/- 1.4 vs peak: 50.5 +/- 16.2) and cortisol levels (basal: 572.5 +/- 112.7 vs peak: 860.5 +/- 102.8. AUC values for ACTH and cortisol were 1627.6 +/- 639.8 and 18364.7 +/- 5661.4, respectively. ACTH and cortisol responses to GHRP-6 and DDAVP did not differ significantly (peak: 45.1 +/- 9.3 vs 50.5 +/- 16.2; AUC: 1235.4 +/- 424.8 vs 1627.6 +/- 639.8). There was a significant positive correlation between peak cortisol values after GHRP-6 and DDAVP administration (r = 0.87, p = 0.001). Our results show that GHRP-6 is able to stimulate ACTH and cortisol release in patients with Cushing's disease. These responses are similar to those obtained after DDAVP injection. These findings could suggest the hypothesis that both peptides act by similar mechanisms, either at hypothalamic or pituitary level.
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Hormona Adrenocorticotrópica/metabolismo , Síndrome de Cushing/metabolismo , Hidrocortisona/metabolismo , Oligopéptidos/farmacología , Adolescente , Adulto , Desamino Arginina Vasopresina/farmacología , Femenino , Hormonas/farmacología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Reinvestigation of the extract of the ascidian Didemnum granulatum collected on the Brazilian coastline led to the isolation of two minor compounds, granulatimide (2) and 6-bromogranulatimide (3), which have been identified by analysis of their spectroscopic data. The isolation of 2 and 3 from D. granulatum corroborates previous assumptions about the occurrence of granulatimide as a natural product.
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Alcaloides/aislamiento & purificación , Urocordados/química , Alcaloides/química , Animales , Brasil , Modelos QuímicosRESUMEN
Serum TSH levels are often paradoxically elevated in patients with hypothyroidism due to Sheehan's syndrome. To investigate this apparent discrepancy, the biological activity and glycosylation of serum TSH were studied in 9 untreated patients with Sheehan's syndrome and 11 normal controls. TSH bioassay was based on cAMP generation, measured by RIA, in a culture system of CHO cells transfected with recombinant human TSH receptor. The oligosaccharide branching of TSH was studied by Con A lectin affinity chromatography, which discriminates TSH isoforms according to their mannose content, and the sialic acid content of TSH was studied by Ricinus communis affinity chromatography in combination with enzymatic removal of sialic acid with neuraminidase treatment. TSH bioactivity was expressed as the ratio between biological and immunofluorometric assays (B/I). Bioactive TSH concentrations were calculated by multiplying serum TSH intrinsic bioactivity by serum immunoreactive TSH concentration (B/I x I). Serum free T(4) (FT(4)) levels were lower in patients than in controls (3.7 +/- 0.4 vs. 14.0 +/- 0.9 pmol/L, respectively; P < 0.0001). Circulating immunoreactive TSH was higher in patients with Sheehan's syndrome than in controls (3.8 +/- 0.8 vs. 1.8 +/- 0.2 mU/L, respectively; P = 0.01). In contrast, TSH B/I was significantly decreased in Sheehan's patients compared with controls (0.6 +/- 0.4 vs. 1.7 +/- 0.8, respectively; P = 0.003). However, the resultant bioactive TSH concentrations in serum of Sheehan's patients were not significantly different from control values (2.1 +/- 0.6 vs. 3.0 +/- 0.4; P = 0.25). A significant correlation was found between the bioactive TSH concentrations and serum FT(4) levels in patients with Sheehan's syndrome (r = 0.66; P = 0.05), but not between serum immunoreactive TSH and FT(4) levels (r = 0.21; P = 0.59) or between intrinsic TSH bioactivity and FT(4) levels (r = 0.56; P = 0.12). The Con A chromatography of serum TSH showed a similar distribution (0.3 < P < 0.5) of unbound, weakly bound, and firmly bound TSH in Sheehan's patients (16%, 38%, and 47%, respectively) and controls (15%, 34%, and 52%, respectively). The ricin chromatography of serum TSH showed a higher proportion of sialylated TSH molecules in Sheehan's patients than in controls (55% vs. 29%; P = 0.02). These results show that circulating TSH in Sheehan's syndrome, albeit increased, has decreased biological activity. The relevance of this finding is supported by the direct correlation between bioactive serum TSH concentrations and circulating FT(4). The reduced intrinsic TSH bioactivity in pituitary hypothyroidism of Sheehan's syndrome results from increased sialylation of TSH.
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Hipopituitarismo/sangre , Hipopituitarismo/complicaciones , Hipotiroidismo/etiología , Tirotropina/sangre , Adulto , Bioensayo , Carbohidratos/análisis , Carbohidratos/fisiología , Estudios de Casos y Controles , Femenino , Glicosilación , Humanos , Inmunoensayo , Masculino , Persona de Mediana Edad , Ácido N-Acetilneuramínico/metabolismo , Valores de Referencia , Tirotropina/química , Tirotropina/metabolismo , Tiroxina/sangreRESUMEN
BACKGROUND: One of the causes of combined pituitary hormone deficiency (CPHD) is represented by Prophet of Pit-1 (PROP-1) gene inactivating mutations. This disorder is generally characterized by GH, TSH, prolactin (PRL), and gonadotropin deficiency, but recent papers have described a concomitant alteration of the corticotrope function. OBJECTIVE: To make a detailed investigation of the hypothalamic-pituitary-adrenal axis in two sisters with PROP-1 gene mutations. PATIENTS: Two female siblings (17 and 16 years old) with CPHD, belonging to a Brazilian family of consanguineous parents, presented with growth retardation and central hypothyroidism during childhood, and showed central hypogonadism at the age of puberty. No clear clinical symptoms and signs of hypocortisolism were present. METHODS: GH, TSH, free thyroxine, total tri-iodothyronine, PRL, LH, FSH, ACTH and cortisol were measured in basal condition and after appropriate testing. The molecular study was performed by PCR amplification and sequencing analysis of PROP-1 gene. RESULTS: Both patients showed GH, PRL, LH and FSH deficiencies, associated with absent responses to an insulin tolerance test (ITT), TRH and GnRH injection. Circulating concentrations of TSH were normal in basal conditions, but failed to respond to a TRH test. Plasma ACTH concentrations were normal, but serum cortisol concentrations were below the lower limit of the normal range, showing a trend to decrease during 6 years of follow-up. The serum ACTH response to ITT was impaired, whereas its response to CRH was normal and prolonged. The cortisol response to both tests, and to the ACTH test, was clearly impaired. In both sisters, the genetic analysis showed the presence of a homozygous 2-bp deletion (296delGA) of PROP-1 gene, which results in the synthesis of a protein with no residual functional activity. CONCLUSION: In addition to GH, TSH, PRL and gonadotropin deficiency, patients with PROP-1 gene mutations can present with late-onset central hypocortisolism, possibly beause of the lack of important paracrine factors normally produced by the cells surrounding the corticotropes and absent in the pituitary of these patients, or because of progressive corticotrope apoptosis. This finding indicates the need for life-long endocrine monitoring of PROP-1-deficient patients.
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Proteínas de Homeodominio/genética , Hidrocortisona/deficiencia , Hipopituitarismo/genética , Hormonas Hipofisarias/deficiencia , Adolescente , Linaje de la Célula , Femenino , Humanos , Hidrocortisona/sangre , Hipopituitarismo/metabolismo , Mutación , Fenotipo , Hormonas Hipofisarias/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
OBJECTIVE: The effects of GH therapy on thyroid function among previous reports have shown remarkable discrepancies, probably due to differences in hormone assay methods, degree of purification of former pituitary-derived GH preparations, dosage schedules, diagnostic criteria, patient selection, duration of treatment and study design. These considerations motivated us to investigate whether and how GH replacement therapy changes serum thyroid hormone levels, including the much less studied rT3 levels, in a group of unequivocally GH-deficient children receiving long-term recombinant human GH therapy. PATIENTS AND DESIGN: Twenty clinically and biochemically euthyroid children were studied in two therapeutic conditions: on GH replacement therapy for at least 6 months and without GH replacement, either before GH was started or after GH was withdrawn for 30-60 days. Eight patients were on thyroxine replacement treatment and thyroxine doses were kept constant during the study. Blood was collected before and after 15, 20 and 60 minutes of TRH administration in both therapeutic conditions (with GH and without GH). MEASUREMENTS: Concentrations of thyroid hormone levels were determined only in sera obtained before TRH administration. FT4, T3 and TSH were measured by immunoflourimetric assays and rT2 was measured by immunoradioassay. RESULTS: Patients were classified into two groups, according to basal TSH levels: group I (TSH > 0.4 mU/l, n = 12) and group II (on thyroxine and TSH < 0.05 mU/l, n = 8). In both groups, serum FT4 levels decreased (17. 0 +/- 1.1 vs. 14.3 +/- 0.9 mU/l, P < 0.001, and 18.0 +/- 1.7 vs. 14. 2 +/- 1.7 mU/l, P < 0.01, respectively), serum T3 levels increased (1.8 +/- 0.1 vs. 2.4 +/- 0.2 nmol/l, P < 0.001, and 1.9 +/- 0.3 vs. 2.4 +/- 0.2 nmol/l, P < 0.05, respectively), and serum rT3 levels decreased (0.35 +/- 0.03 vs. 0.25 +/- 0.03 nmol/l, P < 0.01, and 0. 48 +/- 0.06 vs. 0.34 +/- 0.06 nmol/l, P < 0.01, respectively). Basal (3.2 +/- 0.50 vs. 2.6 +/- 0.72 mU/l, P = 0.28, paired t-test), TRH-stimulated peak TSH levels (13.9 +/- 5.3 vs. 15.9 +/- 8.0 mU/l, P = 0.35, paired t-test) and TRH-stimulated TSH secretion, expressed as area under the curve (609 +/- 97 vs. 499 +/- 53 mU/l.minutes-1, P = 0.15, paired t-test), remained unchanged during GH replacement in group I patients. Low serum FT4 and high serum T3 levels were observed in only one patient each, but low serum rT3 levels were found in six patients (four in group I and two in group II) during GH replacement. CONCLUSIONS: These results show that long-term GH replacement therapy in children with unequivocal GHD significantly decreases serum FT4 and rT3 levels and increases serum T3 levels; that these changes are independent of TSH and result from increased peripheral conversion of T4 to T3 and that GH replacement therapy in GH deficient children does not induce hypothyroidism, but simply reveals previously unrecognized cases whose serum FT4 values fall in the low range during GH replacement.
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Trastornos del Crecimiento/etiología , Hormona del Crecimiento/administración & dosificación , Hormona del Crecimiento/deficiencia , Terapia de Reemplazo de Hormonas , Hormonas Tiroideas/sangre , Adolescente , Adulto , Niño , Femenino , Estudios de Seguimiento , Trastornos del Crecimiento/sangre , Trastornos del Crecimiento/tratamiento farmacológico , Humanos , Hipotiroidismo/inducido químicamente , Hipotiroidismo/diagnóstico , Masculino , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangre , Triyodotironina Inversa/sangreRESUMEN
OBJECTIVE: It has previously been shown that patients with postpartum pituitary necrosis (Sheehan's syndrome, SS) have paradoxically increased TSH levels and loss of the nocturnal TSH surge. This study sought to determine the circadian and pulsatile characteristics of TSH secretion underlying those abnormalities. DESIGN AND PATIENTS: Chronobiological and cluster analyses of 24-h TSH profiles were performed in nine SS patients (43-61 years, median = 52 years) and nine healthy female controls (33-47 years, median = 42 years). MEASUREMENTS: Serum concentrations of T3, T4, free T4 (fT4) and cortisol were measured by radioimmunoassay; TSH, GH, PRL and LH were determined by immunometric assays. RESULTS: All patients and controls showed significant circadian TSH rhythms, but the percentage amplitude was decreased (7.5% vs. 21.3%, P < 0.0001) and the acrophase was markedly displaced in SS patients, occurring between 0315 h and 1515 h in seven/nine patients and in two/nine controls (P = 0.057). Patients showed increased total 24-h TSH secretion (6054 +/- 2293 vs. 2193 +/- 340 mU/l/min, mean +/- SE, P = 0.04) due to increased non-pulsatile or tonic 24-h TSH secretion (5631 +/- 2105 vs. 1925 +/- 301 mU/l/min, P = 0.026), but no difference was detected in pulsatile secretion (424 +/- 191 vs. 268 +/- 41, P = 0.82). The contribution of non-pulsatile to total TSH secretion was also increased in SS patients (93.8% vs. 87.6%, P = 0. 002). No significant changes were found in TSH pulse frequency, amplitude, duration or interpeak interval. When cluster parameters were individually analysed in two distinctive 12-h periods corresponding to acrophase and nadir, patients showed increased non-pulsatile TSH secretion in both periods, but no differences were found in pulsatile TSH secretion, pulse frequency or amplitude. The increment of TSH secretion during the acrophase in SS patients was exclusively due to increased non-pulsatile TSH secretion, as opposed to controls who displayed significant increments in both non-pulsatile and pulsatile TSH secretions. CONCLUSIONS: Sheehan's syndrome patients have increased total TSH secretion due to increased tonic TSH secretion. A circadian TSH rhythm is still present in these patients, but shows decreased magnitude and markedly displaced acrophase.
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Ritmo Circadiano , Hipopituitarismo/fisiopatología , Tirotropina/metabolismo , Adulto , Estudios de Casos y Controles , Análisis por Conglomerados , Femenino , Hormona del Crecimiento/sangre , Humanos , Hidrocortisona/sangre , Hormona Luteinizante/sangre , Persona de Mediana Edad , Prolactina/sangre , Tasa de Secreción , Estadísticas no Paramétricas , Tirotropina/sangre , Hormona Liberadora de Tirotropina , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
The indications for colostomies in traumatic lesions of the colon were prospectively analysed in the light of the anatomical and functional impairment, the time that elapsed after the injury and additional risk factors. In the period between January 1981 and June 1986 75 patients were operated for colonic trauma: 39 had gunshot wounds, 29 suffered stab wounds and seven had blunt injuries. Colostomies were indicated in 47 patients that presented the most severe lesions, whereas the other 28 patients underwent primary repair. Infectious complications occurred in 21 cases; they were related to a pre-operative interval of more than 10 hours, severity of colonic lesion (CIS) grade III to V, blood transfusion of more than 2500 ml, the presence of colostomy, and an abdominal trauma index (PATI) of more than 25. Five patients died in consequence of infectious complications (p less than 0.05), all of them suffering from severe injuries. These findings suggest that in acute trauma of the colon after less than 6 hours colostomy is justified when the CIS is III to V, the PATI more than 25, or in hemodinamically unstable patients.