RESUMO
Picotamide both inhibits thromboxane synthetase and acts as a thromboxane antagonist at the receptor level. We investigated the long-term effect of picotamide on urinary albumin excretion (UAE) at rest and induced by exercise in 30 type 2 diabetic patients who were normotensive and had microalbuminuria while at rest. The subjects of our study had a mean age of 52.5 +/- 1.6 years, BMI of 28.5 +/- 0.7 kg/m2, diabetes duration of 9.1 +/- 1.8 years, and HbA1c of 7.0 +/- 0.8%. The study was a randomized double-blind placebo-controlled trial. The patients were randomly allocated to receive for 1 year either picotamide, 300 mg, 3 tablets/day, or placebo, 3 tablets/day. The patients were asked to visit our outpatient clinic after 1, 3, 6, 9, and 12 months of treatment. At all times, blood pressure, microalbuminuria at rest, blood glucose, serum creatinine, serum picotamide, and creatinine clearance were measured; at baseline and after 6 and 12 months, all patients underwent submaximal physical exercise. After 6 months of picotamide, baseline and exercise-induced microalbuminuria were significantly decreased (up to one-third) as compared with the baseline and placebo level, with no further drops at month 12 of picotamide treatment. On placebo treatment, UAE at rest and after exercise was slightly increased compared with baseline values. The effects of picotamide occurred without significant side effects or changes in either blood pressure levels or glycometabolic control. Our study is the first long-term intervention trial in type 2 diabetes showing that an antithromboxane agent is able to decrease microalbuminuria, which in this disease is a dual marker of macro- and microangiopathy. Our findings suggest an important role for thromboxane in the pathophysiology of microalbuminuria in diabetes; moreover, we hypothesize that antithromboxane agents may have a place in the treatment/prevention of both macro- and microvascular complications in type 2 diabetic patients.
Assuntos
Albuminúria/urina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Ácidos Ftálicos/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Tromboxano B2/antagonistas & inibidores , Administração Oral , Albuminúria/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/prevenção & controle , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/prevenção & controle , Método Duplo-Cego , Exercício Físico/fisiologia , Feminino , Seguimentos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Ftálicos/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Tromboxano B2/urina , Fatores de TempoRESUMO
To study the onset of the action of gonadal sex steroids on the GH axis in spontaneous puberty, which is prolonged and sparingly predictable, we present a clinical investigative paradigm in which six previously untreated boys with isolated hypogonadotropic hypogonadism were exposed to progressively higher testosterone levels designed to mimic the androgen environment recognized during the early stages of puberty. We administered three incremental doses of testosterone (25-, 50-, and 100-mg im injections), each over a period of 4 weeks. Studies of overnight pulsatile GH secretion and GH responses to GHRH alone or combined with L-arginine (a functional somatostatin antagonist) were performed before testosterone administration and after each dose of testosterone. Serum testosterone, but not estrogen, levels increased progressively in all subjects during therapy. Deconvolution analysis of GH release profiles disclosed that GH secretory burst mass was stimulated significantly even by 25 mg testosterone. This parameter was not altered further by higher doses of testosterone. Spontaneous GH secretory burst number and amplitude increased significantly only after the 50- and 100-mg testosterone treatments, after which the serum GH response to GHRH and arginine also rose significantly. In contrast, the GH response to GHRH alone was not significantly affected by any dose of testosterone. Serum testosterone levels correlated significantly with the primary parameters of nocturnal GH secretion. In summary, our experimental model suggests that in males even very small increases in circulating testosterone occurring during the earliest stages of puberty are able to amplify pulsatile GH secretion. Our concomitant secretagogue data further suggest that testosterone exerts its action at different sites in the hypothalamo-somatotropic axis, i.e. directly at the pituitary level, and also at hypothalamic loci, possibly increasing both GHRH and somatostatin release.
Assuntos
Arginina/uso terapêutico , Hormônio Liberador de Hormônio do Crescimento/uso terapêutico , Hormônio do Crescimento Humano/metabolismo , Hipogonadismo/metabolismo , Testosterona/sangue , Adolescente , Ritmo Circadiano , Combinação de Medicamentos , Entropia , Hormônios Esteroides Gonadais/sangue , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/urina , Humanos , Hipogonadismo/tratamento farmacológico , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Estudos Longitudinais , Masculino , Fluxo PulsátilRESUMO
Insulin-dependent (type I) diabetic patients are known to have an exaggerated growth hormone (GH) response to GH-releasing hormone (GHRH), which is hypothesized to be due to a decrease in somatostatin tone. The aim of the study was to ascertain the influence of the presence and activity of the autoimmune process involving a key enzyme (glutamic acid decarboxylase [GAD]) in the synthetic pathway of a neurotransmitter regulating somatostatin secretion, ie, gamma-aminobutyric acid (GABA), on the GH response to GHRH alone or combined with an acetylcholinesterase inhibitor, pyridostigmine (PD), in patients with type I diabetes mellitus. Twenty non-obese type I diabetic patients and 17 normal subjects underwent an intravenous (IV) injection of 100 micrograms GHRH(1-29)NH2. Twelve of 20 diabetic subjects and all of the control subjects also underwent a second experimental procedure, administration of 120 mg oral PD 60 minutes before IV injection of 100 micrograms GHRH. Diabetic subjects with serum GAD antibody (GADA) levels more than 3 U (n = 10) showed significantly higher serum GH levels after GHRH injection as compared both with diabetic patients with GADA less than 3 U (n = 10) and with normal controls, whether expressed as absolute or peak values. GH peaks after GHRH were significantly (rs = .46, P < .05) correlated with the level of GADA in the whole population of type I diabetic subjects studied. PD significantly enhanced the GH response to GHRH, in terms of both absolute and peak values, in patients without GADA (n = 6) and in normal subjects. On the contrary, PD failed to enhance the GH response to GHRH in diabetic patients with GADA (n = 6). Our findings suggest that autoimmunity may play a key role in determining the exaggerated GH response to GHRH in type I diabetes mellitus. The mechanism underlying this effect is hypothesized to be the production of antibodies to GAD, a key enzyme in the synthesis of GABA, and in turn a reduced GABAergic stimulatory tone on somatostatin production at the hypothalamic level.
Assuntos
Doenças Autoimunes/complicações , Diabetes Mellitus Tipo 1/imunologia , Glutamato Descarboxilase/imunologia , Hormônio do Crescimento Humano/metabolismo , Adulto , Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Hormônio Liberador de Gonadotropina/sangue , Hormônio do Crescimento Humano/sangue , Humanos , MasculinoRESUMO
The present pilot study investigated the effect of long-term treatment with picotamide on baseline and exercise-induced urinary albumin excretion levels in normotensive patients with type II diabetes mellitus. Six patients with type II diabetes were studied: four patients (two men and two women; mean age, 52 +/- 11 years) were treated for 9 months with picotamide (300 mg, TID) and two patients who did not receive the study medication served as controls. Three of the picotamide-treated patients were given a cycloergometric exercise test at baseline and after 3 and 6 months of therapy to evaluate the effects of the drug on exercise-induced microalbuminuria. Microalbuminuria at rest was measured in all patients at baseline and after 3, 6, and 9 months. At the end of the study, all the picotamide-treated patients demonstrated a significant decrease in microalbuminuria at rest (from 41.7 +/- 12.7 micrograms/min at baseline to 11.8 +/- 3 micrograms/min after 9 months) and after exercise (peak at baseline 103 +/- 36 micrograms/min vs 65.8 +/- 11 micrograms/min after 6 months). Conversely, in the two controls, microalbuminuria at rest increased from 45.1 +/- 0.9 micrograms/min at baseline to 151 +/- 59 micrograms/min at the end of the 9-month study period. (All values given as mean +/- SEM.) In conclusion, long-term administration of picotamide was effective in reducing abnormal exercise-induced microalbuminuria and albuminuria at rest. These findings suggest that long-term treatment with picotamide of normotensive patients with type II diabetes mellitus and incipient nephropathy may slow the progression of the nephropathy in its early stages.
Assuntos
Albuminúria/etiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Ácidos Ftálicos/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Adulto , Albuminúria/metabolismo , Pressão Sanguínea , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Teste de Esforço , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Ftálicos/administração & dosagem , Projetos Piloto , Inibidores da Agregação Plaquetária/administração & dosagemRESUMO
The aim of our study was to evaluate the effect of the iv administration of two different beta 2- receptors agonists, salbutamol and broxaterol, on the growth hormone (GH) response to maximal exercise in 11 patients (8 males and 3 females; age range 18-65 yr; mean +/- SE age 56 +/- 13 yr; BMI 26.2 +/- 1.4 kg/m2) with chronic asthmatic bronchitis. All the subjects underwent four cycloergometric exercise tests (incremental workload until maximal predicted heart rate). At baseline, at maximal exercise, at the end of the recovery period and 60 min after the end of each exercise, blood samples were drawn for the assay of GH, glucose, insulin, lactates, norepinephrine and epinephrine. Two exercises were performed without treatment while the remaining two were performed 60 min after the administration of 400 micrograms of either salbutamol or broxaterol (both diluted in 10 ml of saline) according to a randomized double blind cross-over design. Both exercise tests performed without treatment caused a significant (p < 0.05) and similar GH peak with respect to baseline values (from 0.3 +/- 0.1 micrograms/L to 2.8 +/- 1.3 micrograms/L, mean of the two exercise tests). Salbutamol pretreatment blunted the GH response to exercise which caused a no more significant serum GH peak over the baseline levels (from 0.6 +/- 0.2 micrograms/L to 1.4 +/- 0.6 micrograms/L,). Moreover, broxaterol completely abolished the GH response to exercise (baseline level 0.6 +/- 0.2 micrograms/L; peak levels 0.4 +/- 0.1 micrograms/L). The serum GH peak after exercise + broxaterol was significantly (p < 0.05) lower as compared to exercise + salbutamol. In conclusion, we have demonstrated for the first time that beta 2 stimulation blunts the physiological GH response to maximal exercise in adult human subjects. It can be suggested that changes in brain neurotransmitters, possibly an increase in the alpha-adrenergic tone, are likely to be involved in this endocrine effects of exercise.
Assuntos
Agonistas Adrenérgicos beta/farmacologia , Albuterol/farmacologia , Asma/sangue , Bronquite/sangue , Exercício Físico/fisiologia , Hormônio do Crescimento/sangue , Isoxazóis/farmacologia , Adolescente , Agonistas de Receptores Adrenérgicos beta 2 , Adulto , Idoso , Asma/complicações , Bronquite/etiologia , Doença Crônica , Estudos Cross-Over , Método Duplo-Cego , Teste de Esforço , Feminino , Hormônios/sangue , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The aim of our study was to assess whether there could be any clinical and/or endocrine (spontaneous growth hormone [GH] secretion rate, baseline insulin-like growth factor-1 [IGF-1]) predictors and/or determinants of the acute effects of continuous intravenous infusion of recombinant human GH on hemodynamic parameters in 12 patients with dilated cardiomyopathy and congestive heart failure (CHF). METHODS AND RESULTS: The study involved 12 male patients with chronic CHF (ischemic in 8 patients and idiopathic in 4). Ten patients were in New York Heart Association functional class III or IV and 2 in class II. The first 24 hours were considered the control period; in fact, during the following 24 hours, all the patients underwent intravenous constant pump infusion of recombinant human GH. Blood samples for GH assay were taken every 20 minutes during the first night of the study (from 10 PM to 6 AM). Moreover, blood samples for GH assay were also taken during exogenous GH infusion. Blood samples for IGF-1 assays were taken at 8 AM of each of the 3 days of the study. Pulmonary artery pressure (PAP) and capillary wedge (PCWP) pressure, cardiac index, and arterial blood pressure were measured 30 minutes after right heart catheterization (baseline 1), at the end of the control period (baseline 2), and every 4 hours during GH infusion. A negative correlation has been found between mean nocturnal GH levels and baseline IGF-1 levels (r = -0.47, P =.124) and between mean nocturnal GH levels and both postinfusion absolute (r = -0.67, P <.05) and delta (postinfusion-preinfusion) (r = -0.58; P < 005) IGF-1 levels. No significant correlations have been found between several parameters of liver function (albumin, bilirubin, and pseudocholinesterase) and mean nocturnal GH. However, baseline IGF-1 levels showed a negative significant correlation (r = -0.76, P <.01) with total bilirubin and a positive correlation (r = 0.72, P <.01) with pseudocholinesterase. Baseline IGF-1 levels showed a significant negative correlation with baseline mean PAP (r = -0.68, P <.05) and PCWP (r = -0.70, P <.05) and a positive correlation with baseline cardiac index (r = 0.71, P <.05). Baseline IGF-1 levels also showed a significant negative correlation with absolute mean PAP (r = -0.63, P <.05) and mean PCWP (r = -0.67, P <.05) after GH infusion. After GH infusion, IGF-1 levels also negatively correlated with post-GH infusion mean PAP (r = -0.50, P =.09) and mean PCWP (r = -0.66, P <.05). The positive correlation between either baseline or postinfusion IGF-1 and the postinfusion cardiac index (r = 0.40 and 0.43, respectively) did not reach statistical significance. CONCLUSIONS: GH has acute functional effects on the heart in patients with CHF, including both an increase in myocardial contractility and a decrease in vascular resistances, and among patients with CHF, those with low baseline IGF-1 are likely to have fewer beneficial effects from GH infusion.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hormônio do Crescimento Humano/uso terapêutico , Idoso , Análise de Variância , Cateterismo Cardíaco , Ecocardiografia , Teste de Esforço , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Hormônio do Crescimento Humano/sangue , Humanos , Infusões Intravenosas , Fator de Crescimento Insulin-Like I/análise , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de TempoRESUMO
Insulin dependent (type I) diabetic patients show abnormal growth hormone (GH) secretion. Hexarelin is an analog of GHRP-6 which releases GH in part via somatostatin inhibition. The aim of our study was to evaluate the effects of hexarelin and GHRH, administered either alone or in combination, on GH secretion in 10 type I diabetic and 7 normal men. All the subjects were administered: 1) human GHRH (1-29) NH2 100 micrograms i.v. bolus at 0 min; 2) hexarelin 100 micrograms i.v. bolus at 0 min; 3) hexarelin 100 micrograms + hGHRH 100 micrograms i.v. bolus at 0 min. In type I diabetic patients significantly greater GH responses to GHRH and hexarelin have been observed with normal subjects. Hexarelin caused a significantly (p < 0.05) greater GH response as compared to GHRH in both diabetic and control subjects. After the administration of hexarelin+GHRH, a significant increase in both GH absolute and peak levels as compared to hexarelin or GHRH alone was found in all the subjects. However, the GH responses to the combined stimuli were not significantly different in diabetics as compared to normals; moreover, the interaction of GHRH and hexarelin was synergistic in controls and additive in diabetics. We hypothesize that a reduction in the hypothalamic somatostatin inhibitory tone combined with increased pituitary GH production may be responsible for the pattern of the GH responses to hexarelin and GHRH observed in our type I diabetic patients.
Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Hormônio Liberador de Hormônio do Crescimento/farmacologia , Hormônio do Crescimento Humano/metabolismo , Hipotálamo/fisiopatologia , Oligopeptídeos/farmacologia , Adulto , Glicemia/metabolismo , Sinergismo Farmacológico , Hormônio Liberador de Hormônio do Crescimento/administração & dosagem , Humanos , Cinética , Masculino , Oligopeptídeos/administração & dosagemRESUMO
In our study we assessed the effects of a single i.m. injection of slow-release Lanreotide (30 mg) (SR-L), a new long-acting somatostain analog, on circulating GH levels, baseline cardiac function (M-mode, 2D guided, doppler-echocardiographic study) and cardiopulmonary response to exercise (cycloergometric test, performed using a computer drived, electrically braked cycle ergometer), tested at baseline, after 7 and 14 days from the injection in 10 acromegalic patients (5 M, 5 F, mean age 57.7 +/- 3.1 yrs, body mass index (BMI) 27 +/- 0.8 kg/m2, blood pressure 141 +/- 6.5/82 +/- 3 mmHg). SR-L administration decreased GH levels in acromegalic patients (mean +/- SEM) from 16.1 +/- 6.9 to 10.8 +/- 5.1 micrograms/L (p = 0.045) after 7 days and to 11.9 +/- 5 micrograms/L (p = 0.078) after 14 days from the injection. Moreover, we observed a significant (p < 0.05) decrease in systolic blood pressure and heart rate at the 7th (135 +/- 6.1 vs 141 +/- 6.5 mmHg, and 68 +/- 2.1 vs 74 +/- 2.1 bpm) and 14th (137 +/- 6.2 vs 141 +/- 6.5 mmHg, and 72 +/- 2 vs 74 +/- 2.1 bpm) day of the study with respect to the baseline values. After SR-L administration we also found an increase in ejection fraction (69 +/- 2 vs 63 +/- 2.3% at 7th day, p = 0.006; 65 +/- 2.3 vs 63 +/- 2.3% at the 14th day, p = 0.027) and shortening fraction (40.8 +/- 1.8 vs 36.6 +/- 1.9% at 7th day, p = 0.005; 38.7 +/- 1.8 vs 36.6 +/- 1.9% at the 14th day, p = 0.045). The positive acute cardiac response to SR-L injection was also demonstrated by the increase in A/E velocity ratios at 7th (1.14 +/- 0.1 vs 0.98 +/- 0.07, p = 0.016) and 14th (1.04 +/- 0.08 vs 0.98 +/- 0.07, p = 0.008) day of the study. After SR-L injection, exercise capacity and VO2 at anaerobic threshold were also increased with respect to the baseline test: 61.1 +/- 8.2 vs 38.9 +/- 6.8 watts (p = 0.002) and 1012.4 +/- 71.5 vs 915.3 +/- 77.8 mL/min (p = 0.033) after 7 days, and 61.4 +/- 7.2 vs 38.9 +/- 6.8 watts (p = 0.002) and 1010.1 +/- 62.5 vs 915.3 +/- 77.8 mL/min (p = 0.010) after 14 days from the injection. In conclusion, these results suggest that in acromegalic patients: (1) SR-L causes a rapid improvement in baseline cardiac function and in cardiopulmonary performance during exercise in acromegaly; (2) the endocrine (decrease in GH levels) and echocardiographic responses to SR-L are maximal after 7 days from the injection, whereas the effect of SR-L on the exercise performance are longer lasting.
Assuntos
Acromegalia/fisiopatologia , Sistema Cardiovascular/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/fisiopatologia , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/farmacologia , Somatostatina/análogos & derivados , Acromegalia/sangue , Acromegalia/tratamento farmacológico , Acromegalia/metabolismo , Adulto , Idoso , Limiar Anaeróbio/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Sistema Cardiovascular/metabolismo , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/farmacologia , Preparações de Ação Retardada/uso terapêutico , Exercício Físico/fisiologia , Feminino , Testes de Função Cardíaca , Hormônio do Crescimento Humano/sangue , Humanos , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/efeitos adversos , Peptídeos Cíclicos/uso terapêutico , Testes de Função Respiratória , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Somatostatina/farmacologia , Somatostatina/uso terapêutico , Fatores de TempoRESUMO
Hexarelin (HEX) is a new synthetic analog of the Growth Hormone releasing peptides and is stronger than GHRH in releasing GH in vivo. No information is available on the effect of food ingestion on HEX-induced GH secretion. On the other hand, we have previously demonstrated that food intake at lunchtime in normal subjects has an inhibitory effect on the GH response to GHRH. The aim of the present study was to investigate the effect of food ingestion on GH secretion induced by HEX as compared to GHRH in six normal men (aged 23-29 years) and six normal women (aged 24-29 years). The body weights for all subjects were within 120% of their ideal body weight, according to their sex and age. Our data confirm that HEX is much more powerful than GHRH in inducing GH release in humans, both in the fasting state (GH-AUC: 3010 +/- 695 after HEX, vs. 1339 +/- 281 after GHRH, microg/L/120 min; p<0.06) and after a meal (GH-AUC: 1523 +/- 121, after HEX, vs. 309 +/- 61, after GHRH, microg/L/120 min; p<0.06). Moreover, our study shows that food intake partially blunts the fasting GH response to HEX (GH-AUC: 3010 +/- 695 after HEX, in fasting state, vs. 1523 +/- 121 after HEX, after meal, microg/L/120 min; p<0.06; mean inhibition of AUC 41.02 +/- 7.96%), whereas it nearly abolishes the GH response to GHRH in the same subjects (GH-AUC: 1339 +/- 281 after GHRH, in fasting state, vs. 309 +/- 61 after GHRH, after meal, microg/L/120 min; p<0.06; mean inhibition of AUC 70.31 +/- 6.22%). In conclusion, our study confirms that HEX acts differently from GHRH; the GH releasing effect of HEX could be only partially influenced by the physiological metabolic or neuroendocrine food-related modifications.