Vasopressin and Its Analogues: From Natural Hormones to Multitasking Peptides.

Human neurohormone vasopressin (AVP) is synthesized in overlapping regions in the hypothalamus. It is mainly known for its vasoconstricting abilities, and it is responsible for the regulation of plasma osmolality by maintaining fluid homeostasis. Over years, many attempts have been made to modify this hormone and find AVP analogues with different pharmacological profiles that could overcome its limitations. Non-peptide AVP analogues with low molecular weight presented good affinity to AVP receptors. Natural peptide counterparts, found in animals, are successfully applied as therapeutics; for instance, lypressin used in treatment of diabetes insipidus. Synthetic peptide analogues compensate for the shortcomings of AVP. Desmopressin is more resistant to proteolysis and presents mainly antidiuretic effects, while terlipressin is a long-acting AVP analogue and a drug recommended in the treatment of varicose bleeding in patients with liver cirrhosis. Recently published results on diverse applications of AVP analogues in medicinal practice, including potential lypressin, terlipressin and ornipressin in the treatment of SARS-CoV-2, are discussed.

[Influence of preventive use of vasopressin tannate on diabetes insipidus and serum sodium at the early postoperation of craniopharyngioma].

OBJECTIVE: To explore the influence of preventive use of vasopressin tannate on diabetes insipidus and serum sodium at the early postoperation of craniopharyngioma.
 Methods: The data of 83 patients, who underwent unilateral sub-frontal approach resection of craniopharyngioma between 2010 and 2014 by the same senior neurosurgeon, were retrospectively analyzed. The patients were divided into a vasopressin tannate group (used group) and a control group. The diabetes insipidus and serum sodium changes were compared between the two groups.
 Results: Compared with the control group, the incidence of diabetes insipidus decreased at the early postoperation in the vasopressin tannate group (P<0.05). There was high incidence of diabetes insipidus in patients with pituitary stalk excision and tumor close adhesion to the third ventricle floor at the early postoperation (P<0.05). Under such conditions, the incidence of diabetes insipidus in the vasopressin tannate group was decreased compared with the control group (P<0.05). Postoperative hypernatremia occurred in 37 patients (44.6%), and hyponatremia occurred in 60 patients (72.3%), the average time of the occurrence of hpernatremia and hyponatremia was 1.4 and 3.7 days after surgery. Postoperative high serum sodium and low serum sodium appeared alternately in 19 patients (22.9%). There was significant difference in the serum sodium distribution in the first day after surgery in both groups (P<0.05), and the percent of hpernatremia in the vasopressin tannate group was significantly less than that in the control group (P<0.05).
 Conclusion: Preventive use of vasopressin tannate can effectively reduce diabetes insipidus and hypernatremia incidence at the early postoperative stage after microsurgery for craniopharyngioma.

Routine postoperative fluid restriction to prevent syndrome of inappropriate antidiuretic hormone secretion after transsphenoidal resection of pituitary adenoma.

OBJECTIVE: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common problem during the postoperative course after pituitary surgery. Although treatment of this condition is well characterized, prevention strategies are less studied and reported. The authors sought to characterize outcomes and predictive factors of SIADH after implementation of routine postoperative fluid restriction for patients undergoing endoscopic transsphenoidal surgery for pituitary adenoma. METHODS: In March 2018, routine postoperative fluid restriction to 1000 ml/day for 7 days was instituted for all patients who underwent surgery for pituitary adenoma. These patients were compared with patients who underwent surgery for pituitary adenoma between March 2016 and March 2018, prior to implementation of routine fluid restriction. Patients with preoperative history of diabetes insipidus (DI) or concern for postsurgical DI were excluded. Patients were followed by neuroendocrinologists and neurosurgeons, and sodium levels were checked between 7 and 10 days postoperatively. SIADH was defined by a serum sodium level less than 136 mmol/L, with or without symptoms within 10 days after surgery. Thirty-day readmission was recorded and reviewed to determine underlying reasons. RESULTS: In total, 82 patients in the fluid-unrestricted cohort and 135 patients in the fluid-restricted cohort were analyzed. The patients in the fluid-restricted cohort had a significantly lower rate of postoperative SIADH than patients in the fluid-unrestricted cohort (5% vs 15%, adjusted OR [95% CI] 0.1 [0.0-0.6], p = 0.01). Higher BMI was associated with lower rate of postoperative SIADH (adjusted OR [95%] 0.9 [0.9-1.0], p = 0.03), whereas female sex was associated with higher rate of SIADH (adjusted OR [95% CI] 3.1 [1.1-9.8], p = 0.03). There was no difference in the 30-day readmission rates between patients in the fluid-unrestricted and fluid-restricted cohorts (4% vs 7%, adjusted OR [95% CI] 0.5 [0-5.1], p = 0.56). Thirty-day readmission was more likely for patients with history of hypertension (adjusted OR [95% CI] 5.7 [1.3-26.3], p = 0.02) and less likely for White patients (adjusted OR [95% CI] 0.3 [0.1-0.9], p = 0.04). CONCLUSIONS: Routine fluid restriction reduced the rate of SIADH in patients who underwent surgery for pituitary adenoma but was not associated with reduction in 30-day readmission rate.

Recurrent pregnancy-induced diabetes insipidus in a woman with hemochromatosis.

Diabetes insipidus is a rare disorder in pregnant women, predating pregnancy or appearing for the first time during gestation. In pregnancy it usually affects women with HELLP syndrome or acute fatty liver of pregnancy and results from the reduced hepatic degradation of placental vasopressinase leading to its increased activity. Although infiltrative diseases have been found to cause diabetes insipidus in non-pregnant population, very few studies showed that these disorders may manifest for the first time during gestation. We describe here the case of transient diabetes insipidus in two subsequent pregnancies of a female with hemochromatosis. The first symptoms of this disease appeared for the first time at the beginning of the third trimester of her second pregnancy, and diagnosis was established on the basis of typical clinical presentation, confirmed by a water deprivation test. Diabetes insipidus resulted from the increased activity of vasopressinase, caused by hemochromatosis-induced liver dysfunction, the presence of which was confirmed between the pregnancies by liver biopsy and identification of the HFE gene mutation. Subsequent desferrioxamine treatment resulted in a less severe clinical course of diabetes insipidus in the last patient's pregnancy. In both pregnancies, the patient was successfully treated with oral desmopressin, which is resistant to degradation by placental vasopressinase. Although unrecognized pituitary disorders may pose a serious health problem to the mother and fetus, hemochromatosis-induced diabetes insipidus, as the case of our patient demonstrates, if effectively diagnosed and treated, cannot be regarded as a contraindication for pregnancy.

Adult orbital langerhans cell histiocytosis with frontal bone involvement.

A 28-year-old woman presented with a 2-week history of right upper eyelid swelling and intermittent frontal headaches. CT demonstrated an ill-defined superior right orbital mass with adjacent right frontal bone erosion and undeveloped frontal sinuses. The orbital biopsy revealed tissue strongly positive for CD1a and S100, diagnostic of Langerhans cell histiocytosis. The systemic workup was negative for multifocal lesions and for diabetes insipidus. In addition to subtotal resection, the patient was treated with a 6-month course of oral prednisone and intravenous vinblastine.

Desmopressin (dDAVP) incident signals the need for enhanced monitoring protocols.

In this article, the authors highlight the circumstances surrounding the death of a young adult neurosurgical patient, recently reported to ISMP Canada. The incident signals the need for enhanced safeguards for patients receiving desmopressin (also known as dDAVP) and intravenous therapy. The authors present information from a recent ISMP Canada Safety Bulletin relevant to critical care, including an outline of potential contributing factors and suggested recommendations.

Transient Diabetes Insipidus After Discontinuation of Vasopressin in Neurological Intensive Care Unit Patients: Case Series and Literature Review.

BACKGROUND: Arginine vasopressin (AVP) is a common second-line or third-line vasopressor used in critically ill neurosurgical patients. Neurosurgical indications include hyperdynamic therapy for vasospasm, maintenance of cerebral perfusion pressure in patients with intracranial hypertension, and prevention of hypotension in patients with sepsis. CASE DESCRIPTION: A series of 6 neurosurgical patients receiving AVP infusions developed severe but transient diabetes insipidus (tDI) after cessation of AVP. To our knowledge, no previous reports of this phenomenon in neurosurgical patients have been published. We reviewed the clinical histories, intensive care unit treatment, medication administration records, and laboratory values of these patients, and we found recurrent elevated serum sodium and urine output and decreased urine specific gravity after discontinuation of AVP. Resolution of tDI occurred upon resumption of AVP or administration of desmopressin. Elevated serum sodium levels were often severe, resulting in worsened clinical outcomes. When AVP was resumed, tDI typically recurred if AVP was again tapered and discontinued. Routine administration of desmopressin was useful in controlling sodium levels until the tDI resolved. CONCLUSIONS: Recognition of this phenomenon has caused us to change our clinical management of neurosurgical patients receiving AVP. We hypothesize that tDI is caused by downregulation of the V2 receptor mass in the renal distal convoluted tubule and collecting duct cells. When AVP is discontinued, patients develop nephrogenic tDI secondary to decreased V2 receptor binding, which explains why desmopressin is effective in correcting tDI. Future research includes a large prospective study to determine risk factors for tDI, its incidence, and its pathophysiology.

Endonasal transsphenoidal surgery: the patient's perspective-survey results from 259 patients.

BACKGROUND: Patient impressions remain an important yet often overlooked aspect of surgical success. Herein we present postoperative questionnaire results in patients after a standard direct endonasal approach, an extended suprasellar endonasal approach, and a reoperative transsphenoidal surgery for tumor removal with the operating microscope. METHODS: From July 1998 through April 2005, of 452 patients undergoing endonasal surgery, 346 were sent questionnaires, and of these, 259 (75%) completed them. Nasal packing was placed for 24 hours in the first 95 patients but not in the last 357. RESULT: Overall, 73% of patients reported a better experience than expected and 8% worse than expected. A worse than expected overall experience was noted in 15% of patients with nasal packing compared with 5% of patients without packing (P = .001). Of patients with preoperative headache, 49% resolved, 34% somewhat resolved, and 5% worsened. The frequency of rhinological complaints declined from 2 weeks to 3 months postsurgery (P < .001); by 3 months or more postsurgery, 67% to 87% of patients had no rhinological complaints and 1% to 2% had severe complaints. Of 30 patients with prior sublabial surgery, the endonasal procedure afforded easier recovery (87%), less pain (80%), better nasal airflow (79%), and a shorter hospital stay (median 3 vs 5 days) (P < .001). Of 28 patients with complications, the severity of rhinological complaints was similar to those without complications except this subgroup reported greater loss of sense of smell 3 months after surgery (P < .001). CONCLUSIONS: Rhinological recovery is typically rapid and relatively complete after direct endonasal transsphenoidal surgery using both standard and extended suprasellar approaches. Compared with the sublabial route, the endonasal approach is associated with less pain, better nasal airflow, and a shorter hospital stay.

Microsurgical anatomy of perforated arteries in the hypothalamic area.

AIM: This study aimed to investigate the microsurgical anatomy of perforating arteries in the hypothalamic area, which are associated with diabetes insipidus. MATERIAL AND METHODS: A total of 20 adult cadaver heads soaked in formalin were infused with red latex through the carotid artery and vertebral artery, and supplementary perfusion was performed after 1 day. RESULTS: The perforating arteries in the hypothalamic area could be divided into three groups according to their origins, namely, the former, below and outside groups. The former group mainly comprised the perforating arteries near the current communicating arteries. The outside group comprised the perforating arteries from the upper clinoid segment of the internal carotid and posterior communicating arteries. The below group comprised the bottom hypophyseal arteries of the cavernous segment from the internal carotid artery. CONCLUSION: Vascular injuries that occur during surgery can be minimised by understanding the distribution of the aforementioned vessels.

Monitorización domiciliaria de sodio en niños con diabetes insípida y adipsia / Home monitoring of sodium in children with adipsic diabetes insipidus

No disponible

Thiazide-lithium synergy in refractory mood swings.

The unfortunate experience with lithium chloride as a salt substitute in the 1940s still directs the clinical usuage of lithium carbonate to a certain extent. We are still warned that lithium salts should never be used in low-sodium situations (e.g., with thiazide diuretics or salt-restricted diets); however, it has recently been shown that thiazide diuretics may be safely used in the treatment of lithium-induced nephrogenic diabetes insipidus (NDI). The authors recapitulate the dangers inherent in the use of this drug combination and present detailed clinical-pharmacologic data on 13 patients which suggest that thiazides are useful in the treatment of lithium-induced NDI and may actually synergize with lithium to produce improved mood control in some lithium-refractory manic-depressive patients.

Drug-induced diabetes insipidus: incidence, prevention and management.

Drug-induced diabetes insipidus is always of the nephrogenic type, i.e. unresponsiveness of the kidneys to the action of antidiuretic hormone. This condition is easily diagnosed by measuring urinary concentrating capacity during a thirst test (e.g. 12 hours of water deprivation) or by administration of a modified antidiuretic hormone, desmopressin, to demonstrate the renal unresponsiveness. Drug-induced nephrogenic diabetes insipidus is not a common disorder except in patients receiving treatment with lithium salts for affective disorders where it may affect about 10% of patients treated long term (15 years). Drug-induced nephrogenic diabetes insipidus caused by other drugs usually occurs in critically ill patients in intensive care units receiving a multitude of drugs dominated by antimicrobials and cytostatics. A search of the World Health Organization's adverse effect database revealed 359 reports of drug-induced diabetes insipidus. Lithium was the most common cause (159 reports) followed by foscarnet (15) and clozapine (10). Treatment is symptomatic in most patients and the offending drug should be stopped. If urine volumes exceed 4 L/day, treatment with thiazides and amiloride has been advocated, and nonsteroidal anti-inflammatory drugs, such as indomethacin, may be tried in severe cases. Prevention of lithium-induced nephrogenic diabetes insipidus is an important aspect of the treatment of affective disorders. In patients treated long term it appears to be only partly reversible upon lithium discontinuation. Close monitoring of the treatment aiming at 12-hour trough value of 0.4 to 0.6 mmol/L is recommended. Yearly measurement of the urinary volume/day is effective in making both the patient and the physician aware of the development of the drug-induced nephrogenic diabetes insipidus. The condition is a serious adverse effect because of the risk of developing dehydration and aggravation of drug intoxications.

Postoperative endocrine management of pituitary tumors.

Pituitary tumors are common and are often associated with endocrine abnormalities. Furthermore, pituitary surgery itself may result in additional hormonal changes, including impairment of anterior pituitary hormone secretion and, more commonly, abnormalities of ADH regulation. Endocrine management of patients with pituitary or other sellar lesions involves acute hospital-based and longer term office-based evaluation and treatment. In the immediate postoperative period, careful attention must be directed toward sodium and water balance as well as toward recognition of changes in endocrine function. Postoperative measurement of serum hormone levels also helps to determine if resection of a hypersecreting tumor has been successful. To minimize postoperative morbidity, perioperative endocrine assessment and management of patients undergoing pituitary surgery should consist of a team approach, involving both the neurosurgeon and the endocrinologist.

Prophylactic efficacy of desmopressin acetate for diabetes insipidus after hypophysectomy in the dog.

The prophylactic efficacy of desmopressin acetate (DDAVP) on diabetes insipidus (DI) after hypophysectomy was investigated in the dog. In the control group, hypernatremia with a plasma level of 155 mEq/l or higher persisted for 12 hr from the 4th to the 16th hour after hypophysectomy, and symptoms of DI developed within five days after surgery. In the DDAVP treatment group, these changes were not observed, showing that administration of DDAVP (4 microg, installation, twice daily) effectively prevented hypernatremia that develops immediately after surgery and DI-like symptoms that persists for about one week after surgery.

Diabetes prevention and control: National Action Plan for NCD Prevention, Control and Health Promotion in Pakistan.

More than 10% of the adult population in Pakistan suffers from diabetes. The National Action Plan for Non-communicable Disease Prevention, Control and Health Promotion in Pakistan (NAP-NCD) incorporates prevention and control of diabetes as part of a comprehensive and integrated national non-communicable disease (NCD) prevention effort. Building on existing data, the diabetes surveillance process has been integrated with a comprehensive population-based NCD surveillance system using waist circumference as a proxy indicator for the risk of diabetes in the short term; however, the surveillance strategy makes a case for future efforts to upgrade surveillance to allow a more comprehensive assessment incorporating biochemical assessments. The programme focuses on diabetes prevention by maximizing risk factor control as a common theme across the range of NCDs and lays emphasis on integrating prevention of'diabetes and intensified case finding in high-risk groups into health services as part of a comprehensive and sustainable, scientifically valid, culturally appropriate and resource-sensitive Continued Medical Education (CME) programme for all categories of healthcare providers. The programme also focuses on ensuring availability of anti-diabetics (insulin, sulphonylureas, metformin) at all levels of healthcare. Building capacity in the health system and coalitions in support of diabetes prevention has also been regarded as being critical.

[Current technical aspect in transsphenoidal pituitary adenomectomy].

The authors describe several useful surgical techniques from our experiences in transsphenoidal microsurgery for pituitary adenomas. Intentional two-staged transsphenoidal removal with open sella floor and intrasellar drainage is available for most of giant adenomas with suprasellar extension. The open sella floor method and intrasellar drainage after first transsphenoidal adenomectomy accelerate to decrease the suprasellar tumor extension. In four of six patients in our series, macroscopically total selective adenomectomy was achieved by a second transsphenoidal operation without complications. As for extremely small microadenomas, represented in patients with Cushing's disease, stepwise systemic search is required to identify a subcortical microadenoma, preserving postoperative pituitary function. Edge resection around the microadenoma is also necessary for normalization of hormonal hypersecretion and permanent cure.

[Medical management after pituitary surgery].

Although the majority of patients with pituitary tumor, undergoing transsphenoidal microsurgery, have a low incidence of hormonal deficiency after surgery, the endocrinological evaluations should be carefully done before and after surgery. Glucocorticoid replacement is necessary in patients with Cushing's disease during and after surgery as well as those with adrenal insufficiency. Repeated CRF test is useful to assess the secondary adrenal insufficiency of Cushing's disease after surgery. Patients with impaired secretion of both ACTH and TSH should receive glucocorticoid replacement before thyroid hormone replacement in order to avoid adrenal crisis. A combination of CRF, GRF, TRH and GnRH is a safer and more reliable test to evaluate pituitary function than the conventional triple test consisting of insulin, TRH and GnRH, especially in patients predicted to have pituitary-adrenal insufficiency. Diabetes insipidus(DI), immediately after pituitary surgery, should be treated with subcutaneous injection of Pitressin. Even if patients seem to have recovered from DI several days after surgery, they must be monitored closely because of the incidence of triphasic DI. Less attention has been given to replacement for GH deficiency in adults. Recent reports revealed that GH replacement in adults with GH deficiency decreases visceral fat tissue and increases plasma calcium, phosphorus, osteocalcin and procollagen III levels. GH replacement will become more popular even in adults. Many options and technological advantages in the diagnosis and treatment of pituitary tumors have developed in a decade. In the near future, post-operative patients with pituitary tumors must be cared for in view of the "quality of life".

Identification of novel selective V2 receptor non-peptide agonists.

Peptides with agonist activity at the vasopressin V(2) receptor are used clinically to treat fluid homeostasis disorders such as polyuria and central diabetes insipidus. Of these peptides, the most commonly used is desmopressin, which displays poor bioavailability as well as potent activity at the V(1b) receptor, with possible stress-related adverse effects. Thus, there is a strong need for the development of small molecule chemistries with selective V(2) receptor agonist activity. Using the functional cell-based assay Receptor Selection and Amplification Technology (R-SAT((R))), a screening effort identified three small molecule chemotypes (AC-94544, AC-88324, and AC-110484) with selective agonist activity at the V(2) receptor. One of these compounds, AC-94544, displayed over 180-fold selectivity at the V(2) receptor compared to related vasopressin and oxytocin receptors and no activity at 28 other G protein-coupled receptors (GPCRs). All three compounds also showed partial agonist activity at the V(2) receptor in a cAMP accumulation assay. In addition, in a rat model of central diabetes insipidus, AC-94544 was able to significantly reduce urine output in a dose-dependent manner. Thus, AC-94544, AC-88324, and AC-110484 represent novel opportunities for the treatment of disorders associated with V(2) receptor agonist deficiency.