Long-term treatment of acromegaly with bromocriptine.

Seventy-three patients with active acromegaly were treated for three to 25 months with bromocriptine 10-60 mg/day. Seventy-one patients showed symptomatic and objective clinical improvement. This included reduction in excessive sweating, hand and foot size, and the number of headaches; improved facial appearance; and increased energy and libido. Abnormal visual fields became normal in two patients, one of whom had concomitant radiotherapy. Mean circulating growth hormone levels, obtained by averaging serial samples through the day, fell by more than 7 microng/l or became undetectable in 58 patients (79%) but did not reach normal values: only 15 patients had mean levels on treatment of 5 microng/l or less. Twenty-three patients were diabetic before treatment, and glucose tolerance became normal in 15 and improved in a further five. Provided the drug was started slowly side effects were minor when compared with the considerable clinical benefit obtained.     

Long-term bromocriptine treatment and somatostatin in acromegaly

9 active acromegalic patients were treated for 12 months with bromocriptine (Parlodel, Sandoz) in a daily dose of 10 mg, and at the end of this treatment a somatostatin infusion was administered. The glucose tolerance and the serum hGH level were determined, and the changes in the clinical symptoms were evaluated. 7 patients (responder group) reacted favourably to the treatment; the other 2 proved to be non-responders, the hGH increasing as a consequence of bromocriptine treatment. The non-responders were among those patients who reacted to hyperglycaemia with a hGH increase (paradox glucose response). The somatostatin infusion employed in the drug treatment caused a very drastic decrease in the hGH level. The biochemical and clinical changes were not synchronous. The results permit the conclusions that (1) a relatively small dose of bromocriptine has a very good effect in the large majority of acromegalic patients; (2) the behaviour of the glucose response is an important point in the differentiation of the non-responders; (3) with somatostatin infusion during bromocriptine treatment a further considerable hGH decrease may be induced (a role is presumably played in the effect by the substitution of the hypothalamically drug-inhibited somatostatin release by exogenous material); (4) there is not a close parallel between the hGH decrease on bromocriptine treatment and the clinical improvement, which indicates the significance of the peripheral effects of the drug.     

Nelson's syndrome: complete remission with cabergoline but not with bromocriptine or cyproheptadine treatment

A woman affected by Cushing's disease underwent bilateral adrenalectomy followed by radiotherapy of the hypothalamic-pituitary area when she was 18 years old. Thereafter, she used hydrocortisone acetate replacement therapy (35.5 mg divided into two daily doses). At the age of 26 years, the patient exhibited the clinical signs of the Nelson's syndrome, i.e. skin and gingival hyperpigmentation accompanied by amenorrhea, and elevated ACTH plasma levels (2,850 pg/ml, normal range 15-80 pg/ml). The magnetic resonance imaging (MRI) analysis of the sellar region evidenced a pituitary macroadenoma, measuring 14 x 13 mm. The patient was initially treated with cyproheptadine hydrochloride (12 mg/day) for 18 months. There was a partial improvement of the symptoms, with a reduction of the ACTH plasma levels to 112 pg/ml, but without any modification of the tumor mass. Due to sleepiness and weight gain, the cyproheptadine treatment was interrupted and substituted by a cabergoline (0.5 mg twice a week) therapy. Soon after cabergoline was applied an improvement of the clinical symptoms and signs was observed such as a regression of the tumor mass and the normalization of the ACTH plasma titers (38 pg/ml). Later, cabergoline was substituted by bromocriptine (7.5 mg/day) and the plasma levels of ACTH increased again (247 pg/ml), and headache and cutaneous hyperpigmentation were recorded. When cabergoline was reintroduced there was a clinical improvement and normalization of ACTH plasma levels (64 pg/ml). The MRI analysis of the sella region demonstrated a complete remission of the pituitary adenoma. The results obtained show for the first time that a long-term treatment with cabergoline also brings about a complete remission of Nelson's syndrome in the presence of a pituitary macroadenoma.     

Growth-hormone-binding protein in patients with acromegaly.

The present study was undertaken to investigate the possible regulatory effect of chronic exposure to human growth hormone (hGH), in patients with acromegaly, on growth-hormone-binding protein (GH-BP). Nineteen patients with active acromegaly, before, during or after treatment, comprised the subjects of this study. Serum GH was measured by radioimmunoassay and GH-BP by a binding assay with dextran-coated charcoal separation. The specific binding of [125I]hGH (1 ng) obtained with 50 microliters serum was expressed as a percentage of total cpm. To evaluate the impact of the lower GH-BP on GH activity, we studied the effect of acromegalic serum on hGH displacement of [125I]hGH binding to GH receptors in rabbit liver membranes. Compared to normal controls (11.43 +/- 0.37%), the acromegalic patients had low serum levels of GH-BP (5.45 +/- 0.40%; p < 0.001), which correlated negatively with serum GH levels (p < 0.01). In 7 patients, GH-BP normalized within 2-3 months of successful therapy. The lower GH-BP was due to a reduction in binding capacity, whereas binding affinity remained unchanged. Acromegalic serum, with its low GH-BP, resulted in a shift to the left of the GH displacement curve when compared with normal human sera: IC50 values were 7.47 +/- 0.29 and 11.19 +/- 0.84 ng (p < 0.02) for acromegalic and normal human sera, respectively. We conclude that acromegaly is characterized by low levels of GH-BP due to a decrease in serum-binding capacity. The decrease in GH-BP may render the acromegalic serum GH relatively more active in the GH receptor assay.     

Gel filtration studies of serum growth hormone in acromegaly following bromocriptine administration.

Sera of 7 patients with active acromegaly were fractionated by Sephadex G-100 chromatography and the effects of bromocriptine on the concentrations of total growth hormone (hGH) and its different molecular forms studied. Three immunoreactive peaks were observed, corresponding to molecular weights of about 20,000 ('little hGH'), 40,000 ('big hGH'), and more than 100,000 ('big big hGH') Following bromocriptine administration, there was significantly more reduction of 'little hGH' than of 'big big hGH'. Careful interpretation of these changes is required in view of the possible influences of sample storage and handling on hGH heterogeneity. We suggest that either bromocriptine acts differentially on the release of 'little' and 'big big hGH', or that these components differ in their metabolic half-life. However, even the suppression of 'little hGH' is insufficient to explain the clinical response of the disease to bromocriptine.     

The importance of presurgical somatostatin analogue therapy in acromegaly

Different types of treatment, including surgery, medical therapy and radiotherapy, are possible in achieving control of acromegaly. Of the medical therapies available, somatostatin analogues are effective in the majority of patients and can induce pituitary tumour shrinkage. The rationale and outcome of somatostatin analogue treatment before surgery in patients with acromegaly is briefly presented. In summary, the benefits of somatostatin analogues given preoperatively should be considered carefully as optimisation of cardiovascular, respiratory and metabolic functions is clinically relevant for perioperative morbidity. Somatostatin analogues also induce significant shrinkage of GH-secreting pituitary tumours, although this does not seem to be helpful in terms of improved surgical outcome.     

Effects of bromocriptine and cyproheptadine on basal and corticotropin-releasing factor (CRF)-induced ACTH release in a patient with Nelson's syndrome

The effects of bromocriptine, a dopamine agonist, and cyproheptadine, a serotonin antagonist, on basal and corticotropin-releasing factor (CRF)-stimulated ACTH release were investigated in a 40-year-old female patient with Nelson's syndrome. Oral administration of either bromocriptine (2.5 mg) or cyproheptadine (8 mg) caused a marked drop in plasma ACTH levels. Intravenous administration of synthetic ovine (o) CRF (50 micrograms) produced an exaggerated response of plasma ACTH. Short-term (3-week) treatment with either bromocriptine (7.5 mg/day) or cyproheptadine (12 mg/day) resulted in a marked suppression of basal ACTH release. Furthermore, a blunted response of plasma ACTH to oCRF was observed after short-treatment with either drug. However, after a longer period of treatment with cyproheptadine (18-week), plasma ACTH levels rose again and hyperresponsiveness to oCRF was restored to the pretreatment levels. These data indicate that synthetic oCRF is a potent secretagogue for ACTH release in a patient with Nelson's syndrome. It is suggested that bromocriptine and cyproheptadine are effective drugs in reducing basal and CRF-stimulated ACTH release, possibly acting at the pituitary level in this case. However, the apparent refractoriness after chronic treatment with cyproheptadine may limit its therapeutic use in the present case.     

Homocysteine levels in acromegaly patients

Acromegaly is associated with a two to three-fold increase in mortality related predominantly to cardiovascular disease. The excess mortality is associated most closely with higher levels of growth hormone (GH). Survival in acromegaly may be normalized to a control age-matched rate by controlling GH levels; in particular, GH levels less than 2.5 ng/mL are associated with survival rates equal to those of the general population. Hyperhomocysteinemia has also been recognized as a risk factor for cardiovascular disease, yet there are limited data on the prevalence of hyperhomocysteinemia in patients with acromegaly. Eighteen acromegaly patients (7 male, 11 female, mean age 42.8 +/- 11.0 years) in our endocrine clinic consented to having the following tests performed: complete blood count (CBC), thyroid hormones, folic acid, vitamin B12, plasma homocysteine levels, uric acid, fibrinogen, CRP, fasting glucose, insulin, C-peptide, total serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, GH, insulin-like growth factor-1 (IGF-1) and GH levels after an oral glucose tolerance test (OGTT). By history, fourteen had macroadenomas and four had microadenomas; eight had hypertension; two had glucose intolerance, and four had diabetes. Fifteen had had transsphenoidal or transfrontal surgery: two had been cured, but 13 others were taking long-acting octreotide. Five patients had undergone radiotherapy and the acromegaly in two was treated primarily with long-acting octreotide. CBC, thyroid hormone, folic acid, and vit B12 levels were normal in all patients. We divided the patients into two groups according to mean GH levels after an OGTT: Group 1 (GH<2.5 ng/mL, n=10), and Group 2 (GH<2.5 ng/mL, n=8). Comparison of the two groups using Mann-Whitney U testing revealed statistically significant lower levels in Group 1 of the following parameters: GH (1.91 +/- 0.90 vs. 8.58 +/- 5.55 ng/mL, p=0.002), IGF-1 (338.30 +/- 217.90 vs. 509.60 +/- 293.58 ng/dL, p=0.06), GH after an OGTT (1.42 +/- 0.81 vs. 9.01 +/- 4.53 ng/mL, p=0.001), plasma homocysteine (12.85 +/- 4.47 vs. 18.20 +/- 4.99 micromol/L, p=0.05), total cholesterol (164.0 +/- 20.81 vs. 188.0 +/- 22.26 mg/dL, p=0.05) and LDL cholesterol (81.0 +/- 9.64 vs. 116.70 +/- 13.03 mg/dl, p=0.01). Differences between the other parameters were not significantly different. Acromegaly patients with high GH levels after an OGTT have much higher levels of homocysteine than patients with lower GH levels. The role of elevated homocysteine levels as an independent cardiovascular risk factor in the mortality of acromegaly patients should be determined in future studies.     

Therapy with bromocriptine and behavior of various hormones in psoriasis patients

The activity of bromocriptin has been clinically tested on 18 patients suffering from psoriasis. The plasma levels of Human Growth Hormone (HGH), Human Adrenocorticotropic Hormone (ACTH), Thyroid Stimulating Hormone (TSH), Prolactin (PL), Aldosterone and Cortisol were investigated in these 18 patients along with 35 untreated psoriatic patients and 19 normal subjects. Bromocriptin was shown to be effective in 13 of our 18 psoriatic patients. Plasma levels of HGH, ACTH, and Aldosterone, measured in all 53 psoriatic patients, were found to be higher than normal in 11, 26 and 40 patients respectively (HGH and Aldosterone: p less than 0,005; ACTH: p less than 0,001).     

Myocardial perfusion abnormalities in patients with active acromegaly.

Cardiomyopathy is often seen in patients with a long history of acromegaly. In order to screen for perfusion abnormalities, patients with active acromegaly without evidence for coronary heart disease were examined by single photon emission computed tomography (SPECT). The study included a group of 11 strictly selected patients with active acromegaly (7 males and 4 females; age 51 +/- 12 y [mean +/- S.D.]) with elevated age-adjusted IGF-I levels (IGF-I 569 +/- 193 micro g/l; GH 31.2 +/- 56.3 micro g/l) compared to an age- and sex-matched non-acromegalic control group with comparable muscle mass index of the left ventricle (126 +/- 41 active vs. 122 +/- 33 g/m 2 control group) and body mass index (26.6 +/- 2.7 vs. 27.0 +/- 5.0 kg/m 2). To address this issue, myocardial perfusion was investigated by single photon emission computed tomography (SPECT) using a triple head gamma-camera. 70 MBq 201TlCl was injected, and post-stress (from bicycle ergometer) images were obtained. Images were interpreted quantitatively by bull's eye polary map (16 regions of the left ventricle) and were compared to the control group. In the patients with active acromegaly, the mean nuclide uptake of the 16 regions of the left ventricle after bicycle stress examination was lower than in the control group (82.99 +/- 2.85 active vs 85.48 +/- 1.29 control group, p < 0.01). Non-homogeneity of nuclide uptake was defined as the standard deviations of the 16 regions and was higher in patients with active acromegaly (11.11 +/- 2.35 active vs. 8.77 +/- 1.39 control group, p < 0.01). In conclusion, myocardial perfusion is impaired in patients with active acromegaly, thus representing an early stage of cardiac involvement in acromegaly that may be directly mediated by growth hormone excess.     

The distribution of viral blips observed in HIV-1 infected patients treated with combination antiretroviral therapy

Human immunodeficiency virus type 1 (HIV-1) infected patients treated with combination antiretroviral therapy frequently have the level of HIV-1 RNA detectable in plasma driven below the lower limit of detection of current assays, 50 copies ml⁻¹. Patients may continue to exhibit viral loads (VLs) below the assay limit for years, yet on some occasions the VL may be above the limit of detection. Whether these ‘blips’ in VL are simply assay errors or are indicative of intermittent episodes of increased viral replication is of great clinical concern. By analyzing the occurrence of viral blips in 123 treated HIV-infected patients, we show that patients do not share a common probability distribution of blip amplitude and thus reject the hypothesis that blips are solely due to assay variation. Work performed under the auspices of the U.S. Department of Energy.     

Effects of pirenzepine, bromocriptine and their association on basal and GHRH- and TRH-induced GH secretion in acromegaly.

In order to ascertain if pirenzepine (Pz), an antimuscarinic drug, could inhibit GH secretion in acromegaly, 8 patients were submitted to 3 successive treatment courses of 9 days each: Pz, bromocriptine (BRC) and Pz plus BRC. No change in basal levels of GH after Pz administration was seen, but its reduction (p less than 0.05) by BRC was observed. Pz plus BRC did not improve this response. None of these drugs abolished the paradoxical GH response to TRH. In 7 normal controls, Pz suppressed the GH responsiveness to GHRH (p less than 0.001), but not in acromegalic patients. BRC, instead, blunted this response. In conclusion, cholinergic control of GH secretion is altered in acromegaly. Pz, either when administered alone or associated with BRC, is not useful for the treatment of this disease.     

Ribavirin-induced anemia in hepatitis C virus patients undergoing combination therapy

The current standard of care for hepatitis C virus (HCV) infection - combination therapy with pegylated interferon and ribavirin - elicits sustained responses in only ～50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in conjunction with models of viral kinetics, the rational identification of treatment protocols that maximize treatment response while curtailing side effects.     

Dynamics of injected somatostatin in blood of patients with hepatic failure and acromegaly

Plasma somatostatin levels were measured by radioimmunoassay (RIA) at various times after rapid injection into the blood of 4 patients with acromegaly, 4 patients with hepatic failure, and 4 healthy subjects. In contrast to the single peak found in normal and acromegalic individuals, two distinct peaks were observed in each patient with liver failure. The first occurred at about the same time as that observed in the other two groups, but the second occurred about 3 min later. This second peak could not be distinguished immunologically from the intact somatostatin tetradecapeptide. The half-time disappearance of somatostatin in patients with hepatic failure was significantly longer than in the normal subjects. Acromegalic subjects tended to have the shortest half-time disappearance of the injected somatostatin and the highest peak level. The results are consistent with the possibility that altered metabolism and/or binding of somatostatin occurs in hepatic failure and in acromegaly.