Desmopressin, a synthetic analog of vasopressin widely used in the treatment of diabetes insipidus and bleeding disorders, is a representative disulfide-containing peptide therapeutic prepared by Fmoc-based solid-phase peptide synthesis (SPPS). Its unique sequence architecture, particularly the spatial proximity between the N-terminal mercaptopropionic acid residue Mpa(1) and the Tyr(2) residue, provides a distinct structural environment for investigating sequence-dependent side reactions during peptide manufacturing. The tert-butyl (t-Bu) protecting group is widely employed for side-chain protection in Fmoc-based solid-phase peptide synthesis (SPPS). However, under certain reaction conditions, the highly reactive t-Bu[+] carbocation generated during acidic deprotection can participate in nonspecific alkylation, leading to challenging process-related impurities. In this study, we investigated a unique and highly site-selective +56 Da impurity observed during side-chain deprotection. High-resolution MS/MS analysis unambiguously identified this species as a site-selective product arising from the migration of t-Bu from the Tyr(2) side chain to the thiol group of Mpa(1). Based on the structural features of desmopressin, in particular, the spatial proximity between Tyr(2) and Mpa(1), we propose that the formation of this impurity most plausibly proceeds via a vicinal-thiol-induced intramolecular migration mechanism, which competes significantly with the conventional diffusion-controlled carbocation intermediate intermolecular pathway. Strengthening the scavenger conditions failed to eliminate this impurity, further supporting the intramolecular migration mechanism induced by vicinal thiol. This finding accounts for the observed site selectivity that cannot be explained by the conventional carbocation intermediate pathway alone. Guided by these mechanistic insights, we re-evaluated the necessity of Tyr side-chain protection and proposed a "source-elimination" strategy. Experimental validation demonstrated that the use of unprotected Fmoc-Tyr-OH (free phenolic hydroxyl) completely suppressed the formation of the t-Bu migration impurity and improved the crude peptide purity to 93.5%. Overall, this study elucidates the formation mechanism of t-Bu migration impurities and provides a broadly applicable, mechanism-driven strategy for process optimization in solid-phase peptide synthesis. While this study focuses on the desmopressin system, the findings highlight a proximity-driven reactivity pattern that may be relevant to other thiol-containing peptide sequences.

An intraoperative ACTH monitoring during resection of hormone-secreting neuroendocrine neoplasms remains a subject of a debate. We present the case of a 36-year-old man with clinical and biochemical features of ACTH-dependent hypercortisolism. Dynamic endocrine testing, including the high-dose dexamethasone suppression test, metyrapone test, and desmopressin stimulation test resulted in inconclusive results, precluding clear differentiation between Cushing's disease and ectopic Cushing's syndrome. Pituitary imaging revealed no definite focal lesion, whereas chest imaging detected a small pulmonary nodule along with an incidental adrenal adenoma. Taking into account rapid clinical course and the severity of clinical symptoms surgical resection of the lung lesion was undertaken with intraoperative ACTH monitoring. Due to compilation of factors patient was sent to thoracic surgery without delay. A transient ACTH surge was observed during first stage tumor excision and, even though intraoperative pathological and surgical findings indicated the complete tumor resection, which contributed to the decision to extend the procedure to an upper lobectomy, after which a marked and sustained decline in ACTH concentrations was observed. Histopathological examination confirmed a typical pulmonary carcinoid tumor, and surgical treatment resulted in clinical and biochemical remission, followed by gradual recovery of the hypothalamic-pituitary-adrenal axis. This case highlights the limitations of dynamic testing and imaging in ECS, particularly in indolent presentation, and underscored the potential value of intraoperative ACTH monitoring as an adjunctive tool for tumor localization and surgical decision-making.

Coagulopathy after traumatic brain injury (TBI) is multifactorial and dynamic, with major implications for hemorrhagic progression and outcome. Platelet dysfunction is an underrecognized component that may occur despite preserved platelet count. For the purpose of this point of view, platelet dysfunction refers to any measurable impairment in agonist-induced aggregation, receptor-pathway responsiveness [adenosine diphosphate (ADP)/P2Y12 and arachidonic acid (AA)/ cyclooxygenase-1 (COX-1) axes], or platelet contribution to whole-blood-clot strength, occurring disproportionate to or in the absence of thrombocytopenia. Functional impairment can appear early and has been associated with TBI severity, intracranial hemorrhage progression, transfusion requirements, and mortality. Conventional coagulation tests and platelet count are insufficient to identify this phenotype. Platelet function assays, including thromboelastography (TEG) with platelet mapping, may help characterize selected high-risk patients. However, the evidence remains largely observational, thresholds are heterogeneous, interassay concordance is poor, and platelet transfusion or desmopressin should not be regarded as routine interventions. This point of view reframes platelet dysfunction after TBI as a dynamic hemostatic phenotype and argues for prospective phenotype-guided trials.

Hematoma expansion (HE), an increase in bleeding into the brain, is a modifiable cause of disability and death after intracerebral hemorrhage (ICH). Some specialized hemostatic biomarkers are associated with HE. Widely available hemostatic biomarkers could improve our understanding of HE and lead to targeted treatments.

Arginine vasopressin deficiency (AVP-D) is an uncommon disorder caused by deficient vasopressin production due to hypothalamic or pituitary gland dysfunction resulting in hypotonic polyuria, whose etiology oftentimes remains elusive. We present the case of a 20-year-old male patient evaluated for polyuria and polydipsia. Laboratory evaluation demonstrated hypernatremia, elevated serum osmolality, and inappropriately dilute urine with symptomatic improvement following initiation of desmopressin, consistent with AVP-D. Initial pituitary magnetic resonance imaging (MRI) showed a small enhancing lesion with pituitary stalk thickening (PST), raising concern for inflammatory or infiltrative etiologies. Extensive autoimmune and pituitary infiltrative disease work-up was unrevealing, and serial imaging remained inconclusive. Given diagnostic uncertainty, a transsphenoidal pituitary biopsy was performed, which proved consistent with a germinoma with evidence of human chorionic gonadotropin secretion. Subsequent staging studies, including spinal MRI and cerebrospinal fluid analysis, raised concern for possible disseminated disease. The patient was treated with craniospinal irradiation and continues close multidisciplinary follow-up for hypopituitarism and AVP-D. This case highlights the need for continued surveillance in patients presenting with AVP-D and nonspecific imaging findings, as early identification of etiology is critical for timely treatment and optimal outcomes.

Diabetes insipidus (DI) is a rare but significant and life-threatening complication of metastatic breast cancer, typically arising when cancer spreads to the pituitary gland. This condition results from impaired secretion or action of antidiuretic hormone (ADH) or arginine vasopressin (AVP), leading to symptoms including excessive urination and thirst. The posterior lobe of the pituitary and the infundibulum are most susceptible to metastatic involvement due to their direct arterial blood supply, making them more accessible to circulating tumor cells. This phenomenon explains why DI can be a manifestation of pituitary metastases. We report the case of a patient who presented with a five-week history of projectile vomiting, dizziness, blurred vision, headache, insatiable thirst, and nocturia. She reported urinating up to 12 times at night such that she struggled to sleep and would end up having daytime lethargy and fatigue. Biochemical evaluation demonstrated hyperosmolar serum, low urine osmolality, and low urine sodium, consistent with central DI. MRI revealed a pituitary stalk and suprasellar metastases with multiple new cerebral and cerebellar lesions. The patient underwent a desmopressin challenge leading to rapid improvement in polyuria and an increase in urine osmolality. Desmopressin confirmed an intact renal response, establishing the diagnosis of cranial DI secondary to pituitary metastases. Despite symptomatic benefit, her overall condition deteriorated due to progressive intracranial and systemic disease. She subsequently received whole-brain radiotherapy and palliative care but died three months after the diagnosis of DI. This case highlights central DI as a rare but clinically important manifestation of pituitary metastases in metastatic breast cancer. Prompt recognition and endocrine replacement, particularly with desmopressin, can provide meaningful symptomatic relief even when prognosis remains poor. Early multidisciplinary involvement, including endocrinology, oncology, radiology, and palliative care, is essential for optimizing quality of life in such complex cases.

Overcorrection is a frequently encountered issue in the treatment of severe hyponatremia, which is defined as a serum sodium concentration below 120-125 mmol/L in symptomatic patients. Severe hyponatremic symptoms, including persistent vomiting, cardiorespiratory arrest, seizures, and reduced consciousness, clearly indicate the use of hypertonic (e.g., 3%) saline infusion to immediately elevate serum sodium levels. In the chronic phase, however, overcorrection is a major concern because an overly rapid increase in serum sodium concentration is an important cause of osmotic demyelination syndrome (ODS). Although risk groups for ODS are well known, saline infusion and water diuresis are 2 common factors underlying the overcorrection of hyponatremia. We propose that isotonic saline initially be infused (1 mL/kg/h) when encountering hyponatremic patients with moderately severe symptoms, such as confusion, headache, or nausea. Although this empirical therapy may not be consistent with current guidelines, it may reduce the risk of overcorrection and be effective in cases with unrecognized hypovolemia or waning vasopressin hyperactivity. We believe that hypertonic saline should be reserved for patients with severely symptomatic hyponatremia. In practice, urine sodium and osmolality should then be measured, along with follow-up serum sodium levels. Subsequent intravenous fluids can be selected according to the response of serum sodium levels and the differential diagnosis of hyponatremia. Because water diuresis is a critical contributor to overcorrection, urine output and urine sodium, potassium, and osmolality should be monitored during fluid therapy. Appropriate use of 5% dextrose in water and/or desmopressin may be necessary to re-lower serum sodium levels.

Arginine vasopressin deficiency (AVP-D) is an endocrine disorder characterized by dilute, non-osmotic polyuria and hypernatremia, caused by a deficiency of antidiuretic hormone (ADH). Drug resources indicate that food may reduce absorption of oral desmopressin (DDAVP). However, it reportedly does not affect pharmacodynamics; therefore, no precautions are currently advised regarding food intake or tube feeding (TF). We present a case in which severe polyuria and hypernatremia developed after TF was initiated in a patient receiving oral DDAVP for AVP-D, which was corrected upon switching to subcutaneous DDAVP, suggesting TF-induced enteral DDAVP malabsorption.