Somatostatin analogs which define the role of the lysine-9 amino group

Acromegaly is a rare disease due to chronic excess growth hormone (GH) and IGF-1. Aryl hydrocarbon receptor interacting protein (AIP) mutations are associated with an aggressive, inheritable form of acromegaly that responds poorly to SST2-specific somatostatin analogs (SSA). The role of pasireotide, an SSA with affinity for multiple SSTs, in patients with AIP mutations has not been reported. We studied two AIP mutation positive acromegaly patients with early-onset, invasive macroadenomas and inoperable residues after neurosurgery. Patient 1 came from a FIPA kindred and had uncontrolled GH/IGF-1 throughout 10 years of octreotide/lanreotide treatment. When switched to pasireotide LAR, he rapidly experienced hormonal control which was associated with marked regression of his tumor residue. Pasireotide LAR was stopped after >10 years due to low IGF-1 and he maintained hormonal control without tumor regrowth for >18 months off pasireotide LAR. Patient 2 had a pituitary adenoma diagnosed when aged 17 that was not cured by surgery. Chronic pasireotide LAR therapy produced hormonal control and marked tumor shrinkage but control was lost when switched to octreotide. Tumor immunohistochemistry showed absent AIP and SST2 staining and positive SST5. Her AIP mutation positive sister developed a 2.5 cm follicular thyroid carcinoma aged 21 with tumoral loss of heterozygosity at the AIP locus and absent AIP staining. Patients 1 and 2 required multi-modal therapy to control diabetes. On stopping pasireotide LAR after >10 years of treatment, Patient 1’s glucose metabolism returned to baseline levels. Long-term pasireotide LAR therapy can be beneficial in some AIP mutation positive acromegaly patients that are resistant to first-generation SSA.

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Heart arrhythmias and conduction disorders in patients with acromegaly: the role of cardiac magnetic resonance imaging

Terapevticheskii arkhiv ◽

10.26442/00403660.2020.10.000787 ◽

2020 ◽

Vol 92 (10) ◽

pp. 70-77

Author(s):

K. V. Melkozerov ◽

E. G. Przhiyalkovskaya ◽

N. V. Tarbaeva ◽

A. A. Almaskhanova ◽

M. D. Kuklina ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Myocardial Fibrosis ◽

Cardiac Mri ◽

Somatostatin Analogs ◽

Cardiac Conduction ◽

Resonance Imaging ◽

Functional Changes ◽

Conduction Disorders

Cardiovascular complications including arrhythmias and cardiac conduction disorders are one of the main reasons of high mortality rate in acromegaly, while they have not been well explored. Aim.To estimate arrhythmias frequency in acromegaly, identify risk factors leading to the development of arrhythmia and cardiac conduction disorder, to determine the role of cardiac MRI in detecting structural and functional changes. Materials and methods.A single-center prospective cohort study, which included 461 patients (151 men and 310 women) with acromegaly, was conducted. All the patients underwent a standard medical examination, including hormonal blood test, electrocardiogram, echocardiography, electrocardiogram daily monitoring. 18 patients with arrhythmias (11 men and 7 women) had cardiac MRI with gadolinium-based contrast. Results.The results of our research show high frequency of arrhythmias and cardiac conduction disorders in patients with acromegaly 42%. Most frequent kinds of arrhythmias and cardiac conduction disorders were sinus bradycardia 19.1% of the cases and conduction disorders of bundle branch blocks 14.5%. Men were more likely to suffer from arrhythmias and cardiac conduction disorders than women (54.2% and 37.4%, respectively,p=0.0005). Not acromegaly activity but duration of the disease was a main risk factor of arrhythmias and cardiac conduction disorders. Patients with arrhythmias had a long anamnesis of acromegaly (10 and 7 years, respectively, p=0.04). Meanwhile, cardiac conduction disorders were commonly observed in the patients who were treated with somatostatin analogs comparing to the patients who didnt undergo this therapy (50% and 38.6% respectively,p=0.004). We showed that 61% of patients with acromegaly and cardiac conduction disorders who underwent magnetic resonance imaging (MRI) had the signs of myocardial fibrosis. The value of the ejection fraction of the left ventricle according to MRI was higher than with echocardiography (p=0.04). Conclusion.Arrhythmias and cardiac conduction disorders are often observed in patients with acromegaly even with remission of the disease. High risk group need careful diagnostic and monitoring approaches. Cardiac MRI is the gold standard for visualization of structural and morphological changes in the heart. Use of cardiac MRI in acromegalic patients expands our understanding of arrhythmias and cardiac conduction disorders in this disease. There are no specific laboratory markers of diffuse myocardial fibrosis, and the role of myocardial fibrosis in the occurrence of cardiac arrhythmias and conduction disorders needs further studying.

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The underestimated role of somatostatin analogs in the NETTER-1 trial

Future Oncology ◽

10.2217/fon-2017-0130 ◽

2017 ◽

Vol 13 (15) ◽

pp. 1287-1289 ◽

Cited By ~ 3

Author(s):

Sara Pusceddu ◽

Roberto Buzzoni ◽

Filippo de Braud

Keyword(s):

Somatostatin Analogs

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Structure of the Second Coordination Sphere of Transition Metal Complexes. II. Substituted Anilines as Ligands

Canadian Journal of Chemistry ◽

10.1139/v71-200 ◽

1971 ◽

Vol 49 (8) ◽

pp. 1218-1223 ◽

Cited By ~ 5

Author(s):

D. R. Eaton ◽

H. O. Ohorodnyk ◽

Linda Seville

Keyword(s):

Coordination Sphere ◽

Methylene Chloride ◽

Chemical Shifts ◽

Cobalt Complex ◽

Cobalt Atom ◽

Amino Group ◽

Substituted Anilines ◽

Second Coordination Sphere ◽

Solvent Molecules

The role of substituted anilines as second coordination sphere ligands of cobalt(II) complexes has been investigated. Chemical shifts of the ligand nuclear magnetic resonance (n.m.r.) spectra arising from pseudo-contact interaction with the paramagnetic cobalt complex have been utilized for this purpose. It has been found that in each case the aniline preferentially occupies a position perpendicular to the three fold symmetry axis of the complex and tends to be aligned with the amino group directed towards the cobalt atom. Electron withdrawing substituents para to the amino group enhance the second coordination sphere binding and electron donating substituents diminish it. These results are consistent with the idea that the structure of the second coordination sphere is determined by electrostatic interaction with the negatively charged ligands comprising the first coordination sphere. There is competition between aniline molecules and solvent molecules for a position in the second sphere with the solvent competing with increasing effectiveness in the series carbon tetrachloride, benzene, and methylene chloride.

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Role of UGT1A1 and ADH gene polymorphisms in pegvisomant-induced liver toxicity in acromegalic patients

Acta Endocrinologica ◽

10.1530/eje-13-0657 ◽

2014 ◽

Vol 170 (2) ◽

pp. 247-254 ◽

Cited By ~ 12

Author(s):

M Filopanti ◽

A M Barbieri ◽

G Mantovani ◽

S Corbetta ◽

V Gasco ◽

...

Keyword(s):

Liver Toxicity ◽

Tertiary Care ◽

Somatostatin Analogs ◽

Liver Function Tests ◽

Regression Analyses ◽

Increased Risk ◽

Adh Gene ◽

Concomitant Medications

ContextHepatotoxicity is one of the most serious adverse effects in acromegalic patients treated with pegvisomant (PEG-V). Recent studies have found an association between this adverse event and the UGT1A1 allele 28 polymorphism associated with Gilbert's syndrome.ObjectiveTo determine whether UGT1A1*28 and alcohol dehydrogenase (ADH) polymorphisms influence liver toxicity during PEG-V treatment.Design and settingMulticenter observational retrospective study conducted in 13 tertiary care endocrinology units in Italy.PatientsA total of 112 patients with active disease resistant to somatostatin analogs (SSTa) and 108 controls were enrolled.InterventionsClinical and biochemical data were recorded by electronic clinical reporting forms. Blood or DNA samples were sent to the coordinating center for genotyping.ResultsNo differences in genotypes between patients and controls were found. During PEG-V therapy liver function tests (LFT), abnormalities and overt hepatotoxicity developed in 17 and 4.5% of patients respectively. Logistic and linear regression analyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratio=1.25;P=0.04) and the number of concomitant medications, other than SSTa (B=3.9;P=0.03). No correlation between LFT alterations and UGT1A1 allele 28 as well as ADH1C and B polymorphisms was found.ConclusionsUGT1A1 allele 28 and ADH1C and B polymorphisms do not predict increased risk of hepatotoxicity during PEG-V therapy. Conversely, patients with multi-therapies and with previous episodes of liver disease should be carefully managed, due to the observed association between these conditions and LFT abnormalities during PEG-V therapy.

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