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Pharmaceutics Dec 2023To meet unmet medical needs, middle-to-large molecules, including peptides and oligonucleotides, have emerged as new therapeutic modalities. Owing to their... (Review)
Review
To meet unmet medical needs, middle-to-large molecules, including peptides and oligonucleotides, have emerged as new therapeutic modalities. Owing to their middle-to-large molecular sizes, middle-to-large molecules are not suitable for oral absorption, but there are high expectations around orally bioavailable macromolecular drugs, since oral administration is the most convenient dosing route. Therefore, extensive efforts have been made to create bioavailable middle-to-large molecules or develop absorption enhancement technology, from which some successes have recently been reported. For example, Rybelsus tablets and Mycapssa capsules, both of which contain absorption enhancers, were approved as oral medications for type 2 diabetes and acromegaly, respectively. The oral administration of Rybelsus and Mycapssa exposes their pharmacologically active peptides with molecular weights greater than 1000, namely, semaglutide and octreotide, respectively, into systemic circulation. Although these two medications represent major achievements in the development of orally absorbable peptide formulations, the oral bioavailability of peptides after taking Rybelsus and Mycapssa is still only around 1%. In this article, we review the approaches and recent advances of orally bioavailable middle-to-large molecules and discuss challenges for improving their oral absorption.
PubMed: 38258058
DOI: 10.3390/pharmaceutics16010047 -
Journal of Clinical Medicine Jan 2024Acromegaly is a rare, chronic disease that involves structural and functional abnormalities of the cardiovascular system. Acromegaly likely affects interactions between...
BACKGROUND
Acromegaly is a rare, chronic disease that involves structural and functional abnormalities of the cardiovascular system. Acromegaly likely affects interactions between the cardiovascular system and the autonomic nervous system (ANS). Therefore, assessing the relationship between sympathetic-parasympathetic balance by analyzing heart rate variability (HRV) and the hemodynamic profile via impedance cardiography (ICG) may be useful in learning the exact nature of interactions between the ANS and the cardiovascular system. The purpose of this study was to assess a possible association between HRV and ICG-based parameters of cardiac function in patients newly diagnosed with acromegaly.
METHODS
This observational cohort study was conducted on 33 patients (18 men, mean age of 47 years) newly diagnosed with acromegaly and no significant comorbidities. A correlation analysis (Spearman's rank coefficient R) of the parameters assessed via ICG and the HRV assessed via 24 h ambulatory electrocardiography was performed. ICG assessments included the following parameters: stroke volume index (SI), cardiac index (CI), acceleration index (ACI), velocity index (VI), and Heather index (HI). The analysis of HRV included both time-domain parameters (pNN50, SDNN, SDSD, rMSSD) and frequency-domain parameters (total power (TP) and its individual frequency bands: low-frequency (LF day/night), high-frequency (HF day/night), and the LF/HF ratio (day/night)).
RESULTS
Frequency-domain HRV analysis showed the following correlations: (1) lower nighttime LF values with higher ACI (R = -0.38; = 0.027) and HI (R = -0.46; = 0.007) values; (2) higher nighttime HF values with higher ACI (R = 0.39; = 0.027) and HI (R = 0.43; = 0.014) values; (3) lower nighttime LF/HF values with higher ACI (R = -0.36; = 0.037) and HI (R = -0.42; = 0.014) values; (4) higher nighttime TP values with higher SI values (R = 0.35; = 0.049). Time-domain parameters of HRV showed a significant correlation only between the nighttime values of SDSD and SI (R = 0.35; = 0.049) and between the daytime and nighttime values of SDNN and HR (R = -0.50; = 0.003 and R = -0.35; = 0.046). In multivariate regression, only ACI was revealed to be independently related to HRV.
CONCLUSIONS
In patients newly diagnosed with acromegaly, the relationship between the sympathetic-parasympathetic balance assessed via HRV and the hemodynamic profile assessed via ICG was revealed. Better function of the left ventricle was associated with a parasympathetic shift in the autonomic balance.
PubMed: 38256528
DOI: 10.3390/jcm13020395 -
Frontiers in Veterinary Science 2023A 14-year-old female domestic short-haired cat with a diagnosed diabetes mellitus and acromegaly was presented for lethargy and dysorexia. On clinical presentation, the...
A 14-year-old female domestic short-haired cat with a diagnosed diabetes mellitus and acromegaly was presented for lethargy and dysorexia. On clinical presentation, the patient showed hyperglycemia, hyperthermia, dull mentation, and dehydration. With the suspicion of an inflammatory or infectious complication of diabetes, she was hospitalized with constant rate infusion of insulin, and empirical ampicillin sulbactam was started. Blood culture revealed positivity for and the septic picture was confirmed by blood analysis, with leukocytosis, neutrophilia, and an increased serum amyloid A concentration. The isolated strain showed susceptibility to every antimicrobial tested. During the second day of hospitalization, the onset of hypoglycemia and hypotension was treated with norepinephrine and glucose in fluid therapy. The cat recovered well and was discharged with insulin and amoxicillin-clavulanate. This is the first case of septicemia associated with in a cat, suspected of developing the infection after contact with natural reservoirs such as rodents or birds. This route of transmission should be highlighted especially in relation to the zoonotic potential of the bacteria.
PubMed: 38249564
DOI: 10.3389/fvets.2023.1261925 -
Diagnostics (Basel, Switzerland) Jan 2024Plurihormonal pituitary neuroendocrine tumors (PitNETs) are rare forms of tumors that express more than one hormone. The most common association is between growth...
Plurihormonal pituitary neuroendocrine tumors (PitNETs) are rare forms of tumors that express more than one hormone. The most common association is between growth hormone (GH) and prolactin (PRL), but other unusual combinations have been reported, such as GH and ACTH. Usually, the clinical dominance in these cases is related to GH hypersecretion. In these cases, immunohistochemistry (IHC) of transcription factors (TFs) is very useful for an accurate diagnosis. We included 42 patients diagnosed with pituitary neuroendocrine tumors (PitNETs): 37 patients with a confirmed diagnosis of acromegaly, and 5 patients with prolactinomas. All patients underwent transsphenoidal surgical intervention. We correlated the immunohistochemical features of plurihormonal PitNETs with clinical, hormonal, and imaging data. Tumor specimens were histologically and immunohistochemically examined. Based on the 2022 WHO classification, using IHC, 13 patients exhibited positive staining for more than one hormone, while unusual combinations like GH + ACTH and PRL + ACTH were also identified in other cases. Unusual cell combinations that produce hormones unrelated histogenetically, biochemically, or through regulatory mechanisms can appear and may display aggressive behavior, persistent disease, and high recurrence. We have not identified a clear correlation with the prognosis of these rare PitNETs.
PubMed: 38248047
DOI: 10.3390/diagnostics14020170 -
Journal of Endocrinological... Jul 2024Pasireotide LAR (PAS-LAR) was released in Italy in 2017 to treat acromegaly patients resistant to SRLs (Somatostatin Receptors Ligands). The long-term follow-up data of... (Observational Study)
Observational Study
OBJECTIVE
Pasireotide LAR (PAS-LAR) was released in Italy in 2017 to treat acromegaly patients resistant to SRLs (Somatostatin Receptors Ligands). The long-term follow-up data of PAS-LAR therapy in Italy are limited. This study aimed to evaluate the efficacy and safety of PAS-LAR in acromegaly.
DESIGN
Patients with acromegaly in PAS-LAR treatment were enrolled in three tertiary Italian endocrinological centers and evaluated by a retrospective observational real-life multicentre study.
METHODS
Patients have been studied before (baseline) and 1, 6, 12, 24 and > 36 months after PAS-LAR start. Clinical, biochemical, and pituitary magnetic resonance data were collected, along with information on adverse events. Acromegaly disease activity was classified according to the IGF-1 index (normal value < 1.0).
RESULTS
Fifty patients (female 23) were enrolled. PAS-LAR treatment (mean follow-up 24 ± 16 months) significantly decreased IGF-1 levels (IGF-1 index baseline vs last visit: 1.9 ± 0.6 vs 1.2 ± 0.6, p < 0.0001). At the last visit, 67% of patients had controlled disease, and 44% showed a decrease in tumor volume. Clinical and biochemical efficacy was observed as early as after 1-month of PAS-LAR treatment (IGF-1 index baseline vs 1-month: 1.9 ± 0.6 vs 1.4 ± 0.7, p < 0.0001). Also, 50% of patients referred headache improvement or disappearance. Fifteen patients discontinued PAS-LAR due to failure of treatment and poor glycaemic control. The prevalence of diabetes increased from 33% at the baseline to 54% at the last visit (p = 0.0072).
CONCLUSION
In real-life settings, PAS-LAR significantly decreases symptoms, IGF-1 levels, and the size of adenoma in patients with acromegaly resistant to SRLs. Beneficial effects may occur early after the first injection.
Topics: Humans; Female; Acromegaly; Male; Somatostatin; Middle Aged; Follow-Up Studies; Retrospective Studies; Adult; Treatment Outcome; Insulin-Like Growth Factor I; Italy; Growth Hormone-Secreting Pituitary Adenoma; Aged; Human Growth Hormone
PubMed: 38244140
DOI: 10.1007/s40618-023-02275-1 -
Journal of Endocrinological... Jun 2024This study aimed to assess the long-term outcome of patients with acromegaly. (Observational Study)
Observational Study
OBJECTIVE
This study aimed to assess the long-term outcome of patients with acromegaly.
DESIGN
This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up.
METHODS
Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population.
RESULTS
A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population.
CONCLUSIONS
Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.
Topics: Humans; Male; Female; Acromegaly; Italy; Middle Aged; Retrospective Studies; Adult; Follow-Up Studies; Aged; Survival Rate; Prognosis
PubMed: 38214852
DOI: 10.1007/s40618-023-02257-3 -
Surgical Neurology International 2023Acromegaly is a rare disease caused by growth hormone (GH) hypersecretion caused by a pituitary neuroendocrine tumor (PitNET). However, some acromegaly patients show...
BACKGROUND
Acromegaly is a rare disease caused by growth hormone (GH) hypersecretion caused by a pituitary neuroendocrine tumor (PitNET). However, some acromegaly patients show normal GH levels, and they can be a pitfall in clinical diagnosis. Moreover, rarely, synchronous true double or multiple PitNETs are encountered. Moreover, these PitNETs increase the risk of a left lesion during surgical exploration.
CASE DESCRIPTION
The patient, who was a 73-year-old female, was referred to our hospital with a chief complaint of headache. Assessment of basal anterior pituitary function revealed a slightly high level of insulin-like growth factor-1 (IGF-1) (standard deviation, 2.4), and her physical findings exhibited mild acromegalic features. The endocrine evaluation confirmed acromegaly and magnetic resonance imaging (MRI) showed a macro PitNET with suprasellar extension. Endoscopic endonasal surgery (EES) was performed to remove the macro PitNET. Although postoperative MRI showed complete removal of the macro PitNET, endocrinological testing indicated no improvement in GH or IGF-1 excess. Pathological examination of the surgical specimen revealed a gonadotropic PitNET. Therefore, we repeated the MRI scan and found a micro PitNET in the thin left normal pituitary gland. A second EES was successfully performed to remove the micro PitNET completely, and both endocrinological and pathological examinations confirmed that the disease was cured.
CONCLUSION
Diagnosing acromegaly with low GH levels requires close monitoring. Double PitNETs are relatively rare and can cause incomplete remission of functional PitNETs.
PubMed: 38213454
DOI: 10.25259/SNI_718_2023 -
Endocrine Connections Mar 2024The aim of this study was to examine the probability of achieving acromegaly disease control according to several patient-, disease- and treatment-related factors...
PURPOSE
The aim of this study was to examine the probability of achieving acromegaly disease control according to several patient-, disease- and treatment-related factors longitudinally.
METHODS
We analyzed data from ACROSTUDY, an open-label, noninterventional, post-marketing safety surveillance study conducted in 15 countries. A total of 1546 patients with acromegaly and treated with pegvisomant, with available information on baseline IGF-1 level, were included. Factors influencing IGF-1 control were assessed up to 10 years of follow-up by mixed-effects logistic regression models, taking into account changing values of covariates at baseline and at yearly visits. Twenty-eight anthropometric, clinical and treatment-related covariates were examined through univariate and multivariate analyses. We tested whether the probability of non-control was different than 0.50 (50%) by computing effect sizes (ES) and the corresponding 95% CI.
RESULTS
Univariate analysis showed that age <40 years, normal or overweight, baseline IGF-1 <300 µg/L or ranged between 300 and 500 µg/L, and all pegvisomant dose <20 mg/day were associated with a lower probability of acromegaly uncontrol. Consistently, in multivariate analyses, the probability of uncontrolled acromegaly was influenced by baseline IGF-1 value: patients with IGF-1 <300 µg/L had the lowest risk of un-controlled acromegaly (ES = 0.29, 95% CI: 0.23-0.36). The probability of acromegaly uncontrol was also lower for values 300-500 µg/L (ES = 0.37, 95% CI: 0.32-0.43), while it was higher for baseline IGF-1 values ≥700 µg/L (ES = 0.58, 95% CI: 0.53-0.64).
CONCLUSION
Baseline IGF-l levels were a good predictor factor for long-term acromegaly control. On the contrary, our data did not support a role of age, sex, BMI and pegvisomant dose as predictors of long-term control of acromegaly.
SIGNIFICANCE STATEMENT
Among factors that could influence and predict the efficacy of pegvisomant therapy in controlling acromegaly, a central role of baseline IGF-1 values on the probability of achieving a biochemical control of acromegaly during the treatment with pegvisomant was identified, in a real-life setting.
PubMed: 38197875
DOI: 10.1530/EC-23-0247 -
JCEM Case Reports Jan 2024Acromegaly is very uncommon, as is non-iatrogenic Cushing syndrome; we discuss a patient who was found to have both a pituitary adenoma causing acromegaly and a...
Acromegaly is very uncommon, as is non-iatrogenic Cushing syndrome; we discuss a patient who was found to have both a pituitary adenoma causing acromegaly and a cortisol-producing adrenal adenoma causing Cushing syndrome within 1 year. She was a healthy, 44-year-old woman who presented with visual changes and was found to have bitemporal hemianopsia and a 3.3-cm pituitary mass along with central hypogonadism, central hypothyroidism, and suppressed adrenocorticotropin and discrepant cortisol. After transsphenoidal resection she had declining, but persistently elevated, insulin-like growth factor 1 (IGF-1), raising concern for persistent acromegaly. She also was experiencing several cushingoid symptoms and was found to have elevated salivary and urinary cortisol. An abdominal computed tomography scan showed a 3.1-cm adrenal adenoma, and she subsequently underwent adrenalectomy. Following adrenalectomy, her cortisol levels normalized, and her IGF-1, growth hormone, and oral glucose tolerance test showed substantial improvement consistent with previous reports linking hypercortisolism and elevated IGF-1 levels. Combinations of pituitary and adrenal disease are seen in a handful of genetic syndromes; however, her clinical presentation and genetics do not fit with known syndromes. This case describes two rare endocrine tumors in one patient and associated limitations of routine laboratory testing.
PubMed: 38192880
DOI: 10.1210/jcemcr/luad145 -
Endocrinology and Metabolism (Seoul,... Feb 2024This review intends to provide the reader with a practical overview of several (patho)physiological conditions in which knowledge of the interplay between growth hormone... (Review)
Review
This review intends to provide the reader with a practical overview of several (patho)physiological conditions in which knowledge of the interplay between growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin is important. This might help treating physicians in making the right decisions on how to intervene and improve metabolism for the benefit of patients, and to understand why and how metabolism responds in their specific cases. We will specifically address the interplay between GH, IGF-1, and insulin in type 1 and 2 diabetes mellitus, liver cirrhosis, and acromegaly as examples in which this knowledge is truly necessary.
Topics: Humans; Growth Hormone; Insulin; Insulin-Like Growth Factor I; Insulin-Like Peptides; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Human Growth Hormone
PubMed: 38192102
DOI: 10.3803/EnM.2024.101