RESUMO
We have previously shown that kidney collecting ducts make vasopressin. However, the physiological role of collecting duct-derived vasopressin is uncertain. We hypothesized that collecting duct-derived vasopressin is required for the appropriate concentration of urine. We developed a vasopressin conditional knockout (KO) mouse model wherein Cre recombinase expression induces deletion of arginine vasopressin (Avp) exon 1 in the distal nephron. We then used age-matched 8- to 12-wk-old Avp fl/fl;Ksp-Cre(-) [wild type (WT)] and Avp fl/fl;Ksp-Cre(+) mice for all experiments. We collected urine, serum, and kidney lysates at baseline. We then challenged both WT and knockout (KO) mice with 24-h water restriction, water loading, and administration of the vasopressin type 2 receptor agonist desmopressin (1 µg/kg ip) followed by the vasopressin type 2 receptor antagonist OPC-31260 (10 mg/kg ip). We performed immunofluorescence and immunoblot analysis at baseline and confirmed vasopressin KO in the collecting duct. We found that urinary osmolality (UOsm), plasma Na+, K+, Cl-, blood urea nitrogen, and copeptin were similar in WT vs. KO mice at baseline. Immunoblots of the vasopressin-regulated proteins Na+-K+-2Cl- cotransporter, NaCl cotransporter, and water channel aquaporin-2 showed no difference in expression or phosphorylation at baseline. Following 24-h water restriction, WT and KO mice had no differences in UOsm, plasma Na+, K+, Cl-, blood urea nitrogen, or copeptin. In addition, there were no differences in the rate of urinary concentration or dilution as in WT and KO mice UOsm was nearly identical after desmopressin and OPC-31260 administration. We conclude that collecting duct-derived vasopressin is not essential to appropriately concentrate or dilute urine.NEW & NOTEWORTHY Hypothalamic vasopressin is required for appropriate urinary concentration. However, whether collecting duct-derived vasopressin is involved remains unknown. We developed a novel transgenic mouse model to induce tissue-specific deletion of vasopressin and showed that collecting duct-derived vasopressin is not required to concentrate or dilute urine.
Assuntos
Desamino Arginina Vasopressina , Túbulos Renais Coletores , Camundongos Knockout , Animais , Túbulos Renais Coletores/metabolismo , Túbulos Renais Coletores/efeitos dos fármacos , Desamino Arginina Vasopressina/farmacologia , Capacidade de Concentração Renal/efeitos dos fármacos , Arginina Vasopressina/metabolismo , Masculino , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Camundongos , Aquaporina 2/metabolismo , Aquaporina 2/genética , Antidiuréticos/farmacologia , Receptores de Vasopressinas/genética , Receptores de Vasopressinas/metabolismo , Camundongos Endogâmicos C57BL , Privação de Água , Concentração Osmolar , Sódio/urina , Sódio/metabolismo , Vasopressinas/metabolismo , BenzazepinasRESUMO
X-linked nephrogenic diabetes insipidus (X-NDI) is a rare congenital disease caused by inactivating mutations of the vasopressin type-2 receptor (AVPR2), characterized by impaired renal concentrating ability, dramatic polyuria, polydipsia and risk of dehydration. The disease, which still lacks a cure, could benefit from the pharmacologic stimulation of other GPCRs, activating the cAMP-intracellular pathway in the kidney cells expressing the AVPR2. On the basis of our previous studies, we here hypothesized that the ß3-adrenergic receptor could be such an ideal candidate. We evaluated the effect of continuous 24 h stimulation of the ß3-AR with the agonist BRL37344 and assessed the effects on urine output, urine osmolarity, water intake and the abundance and activation of the key renal water and electrolyte transporters, in the mouse model of X-NDI. Here we demonstrate that the ß3-AR agonism exhibits a potent antidiuretic effect. The strong improvement in symptoms of X-NDI produced by a single i.p. injection of BRL37344 (1 mg/kg) was limited to 3 h but repeated administrations in the 24 h, mimicking the effect of a slow-release preparation, promoted a sustained antidiuretic effect, reducing the 24 h urine output by 27%, increasing urine osmolarity by 25% and reducing the water intake by 20%. At the molecular level, we show that BRL37344 acted by increasing the phosphorylation of NKCC2, NCC and AQP2 in the renal cell membrane, thereby increasing electrolytes and water reabsorption in the kidney tubule of X-NDI mice. Taken together, these data suggest that human ß3-AR agonists might represent an effective possible treatment strategy for X-NDI.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Masculino , Animais , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Antidiuréticos/farmacologia , Antidiuréticos/uso terapêutico , Capacidade de Concentração Renal/efeitos dos fármacos , Polidipsia/tratamento farmacológico , Polidipsia/etiologiaRESUMO
Introducción: Se ha postulado que el uso de vasopresina tendría efectos beneficiosos en el postoperatorio de cirugía cardiovascular. Objetivo: Evaluar la respuesta a la vasopresina en el postoperatorio (POP) de cirugía de Fontan de nuestra población. Métodos: Estudio de casos y controles anidados en una cohorte retrospectiva. Se incluyeron pacientes con cirugía de Fontan entre 2014 y 2019. Se registraron variables demográficas, datos del cateterismo pre-Fontan, días de asistencia respiratoria mecánica (ARM), necesidad de inotrópicos, diuréticos, diálisis, dieta hipograsa, octreotide, sildenafil y nutrición parenteral total (NPT); balance de fluidos al primer y segundo día POP, necesidad de cateterismo en el POP, días de permanencia de tubo pleural, días de internación, necesidad de reinternación y mortalidad. Se compararon los grupos con y sin vasopresina utilizando la prueba de Mann- Whitney-Wilcoxon test. Se consideró significativa una p < 0.05. Resultados: Del total analizado, 35 pacientes recibieron vasopresina. En el grupo control fueron 58 pacientes con características similares de gravedad sin vasopresina. No se encontraron diferencias en la evolución postoperatoria entre ambos grupos. El grupo con vasopresina recibió en mayor proporción dieta hipograsa. Conclusiones: En nuestra serie el uso de vasopresina no marcó diferencias significativas en términos de morbimortalidad con relación al grupo control (AU)
Introduction: The use of vasopressin has been suggested to have beneficial effects in the postoperative period after cardiovascular surgery. Objective: To evaluate the response to vasopressin in the postoperative period (POP) of Fontan surgery in our population. Methods: Nested case-control study in a retrospective cohort. Patients who underwent Fontan surgery between 2014 and 2019 were included. Demographic variables, pre-Fontan catheterization data, days of mechanical ventilation (MRA), need for inotropics, diuretics, dialysis, low-fat diet, octreotide, sildenafil and total parenteral nutrition (TPN); fluid balance at first and second day POP, need for catheterization at POP, duration of chest tube drainage, days of hospitalization, need for readmission, and mortality were recorded. Groups with and without vasopressin were compared using the Mann-Whitney- Wilcoxon test. A p < 0.05 was considered significant. Results: Of all patients analyzed, 35 received vasopressin. The control group consisted of 58 patients with similar severity characteristics who did not receive vasopressin. No differences were found in the postoperative outcome between the two groups. The vasopressin group received a higher proportion of low-fat diet. Conclusions: In our series the use of vasopressin did not show significant differences in terms of morbidity and mortality compared to the control group (AU)
Assuntos
Humanos , Lactente , Pré-Escolar , Complicações Pós-Operatórias/tratamento farmacológico , Arginina Vasopressina/administração & dosagem , Arginina Vasopressina/uso terapêutico , Técnica de Fontan/efeitos adversos , Antidiuréticos/administração & dosagem , Antidiuréticos/uso terapêutico , Indicadores de Morbimortalidade , Estudos Retrospectivos , Resultado do Tratamento , HemodinâmicaRESUMO
PURPOSE: Evidence on the efficacy of desmopressin in nocturia in patients with neurological diseases is still very limited except for multiple sclerosis (MS). Our aim was to evaluate the efficacy and safety of desmopressin treatment on nocturia in patients with underlying neurological diseases. METHODS: Studies were identified by electronic search of PubMed, Embase, Cochrane, CINAHL, and Google Scholar databases. Studies were considered if they provided information on the effectiveness and safety of desmopressin (1-desamino-8-d-arginine vasopressin, or DDAVP) in the treatment of nocturia and their participants had acquired neurological pathology. Two researchers independently extracted the articles using specified datasets, such as quality-of-study indicators. Statistical meta-analysis was carried out using Review Manager (RevMan) 5.4 statistical software (Cochrane Collaboration). RESULTS: Of a total of 1042 articles in the initial search, 14 studies were included. Most of the published papers were related to MS (n = 7), two were on spinal cord injury, and other conditions were neural tube defect, myelodysplasia, Parkinson's disease, stroke, and multiple system atrophy. Overall, a total of 200 patients (mostly females) were enrolled. Thirteen studies evaluated the intranasal formulation of desmopressin and one study evaluated oral desmopressin. A significant decrease in nocturia episodes was reported in seven studies evaluating this topic. An increase in the maximum hours of uninterrupted sleep was reported in the three studies in which this outcome was assessed. A significant reduction in the volume of nocturnal incontinence was found in one study. Three studies were eligible to include in the meta-analysis. The results showed that desmopressin compared to placebo, significantly reduced nighttime urination (mean difference: -0.75, 95% CI: -1.10 to -0.41; p < 0.00001). The rate of adverse events ranged from 0% to 68.42%. The critical appraisal results for all trials showed that most of the studies had low or moderate quality. CONCLUSIONS: Our results emphasized desmopressin's safety and efficacy in reducing nocturia episodes, with transient adverse effects on neurological patients. However, the data were achieved from low or medium-quality trials, and further well-designed randomized controlled trials are needed.
Assuntos
Esclerose Múltipla , Noctúria , Feminino , Humanos , Masculino , Noctúria/tratamento farmacológico , Noctúria/etiologia , Desamino Arginina Vasopressina/efeitos adversos , Poliúria , Antidiuréticos/efeitos adversos , Resultado do Tratamento , Esclerose Múltipla/tratamento farmacológicoRESUMO
Central diabetes insipidus is a rare disorder characterized by a deficiency of vasopressin. The first line drug to treat this disorder is a synthetic analogue of vasopressin, desmopressin.The primary aim of this retrospective register study was to compare desmopressin dose requirements in patients with acquired and congenital DI, and secondly to assess the influence of BMI on dose requirement and risk of hyponatremia with different drug administrations. We included all patients with suspected DI attending the endocrine department at Rigshospitalet, Copenhagen, Denmark in 2022. We identified 222 patients who were included whereof 130/222 (58.6%) were females and median age was 53 years (IQR 35 to 63). The etiology included 7/222 (3.2%) congenital and 215/222 (96.8%) acquired. After converting nasal and sublingual doses to equivalent oral doses, the median daily dose requirement was 600 µg in patients with congenital etiology compared to 200 µg in patients with acquired etiology (p=0.005). We found no association between BMI and desmopressin dose requirements (p=0.6). During the past 12 months, 66/215 (30.7%) had sodium levels<136 mmol/l including 20/215 (9.3%) with sodium levels<131 mmol/l. No increased risk of hyponatremia was found, when nasal and oral were compared (p=0.9). Daily desmopressin dose requirements were higher in patients with congenital DI compared to patients with acquired DI. However, this result was associated with uncertainty due to the small congenital group. BMI did not influence daily dose requirements and nor did type of administration influence the risk of hyponatremia.
Assuntos
Diabetes Insípido Neurogênico , Diabetes Mellitus , Hiponatremia , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , Diabetes Insípido Neurogênico/tratamento farmacológico , Desamino Arginina Vasopressina/efeitos adversos , Hiponatremia/induzido quimicamente , Hiponatremia/tratamento farmacológico , Antidiuréticos/efeitos adversos , Estudos Retrospectivos , Sódio/uso terapêutico , Diabetes Mellitus/tratamento farmacológicoRESUMO
CONTEXT: Desmopressin orally disintegrating tablets (ODTs) are widely used to treat arginine vasopressin deficiency (AVP-D). However, limited information is available on the dosage regimen; the dosage for each patient is selected based on their response to the initiation dose. OBJECTIVE: To investigate the relationships between clinical characteristics and the daily dose of ODTs and to identify factors that affect ODT dosages. METHODS: This retrospective study included 209 adult patients with AVP-D. Patients were administered ODTs sublingually and instructed to restrict eating and drinking for 30â minutes after taking ODTs using a patient leaflet. ODT dose titration was conducted during hospitalization with close monitoring of urine output, body weight, and serum sodium levels. Multivariable linear regression models were applied to identify clinical factors associated with the daily dose of ODTs at discharge. We also evaluated the dosage at 1 year in 134 patients who were followed up in our hospital. RESULTS: The median daily dose of ODTs at discharge was 90â µg (IQR 60-120â µg). Multivariable linear regression models identified sex, age, and estimated creatinine clearance (eCCr) as significant factors associated with the daily dose of ODTs, with eCCr having the strongest effect. After excluding patients recovering from AVP-D, 71% of those followed up at our hospital took the same daily dose at 1 year after discharge. CONCLUSION: To achieve the safe and stable treatment of AVP-D, the daily dose of ODT needs to be selected based on a patient's sex, age, and eCCr under appropriate sublingual administration by patient education.
Assuntos
Diabetes Insípido Neurogênico , Adulto , Humanos , Diabetes Insípido Neurogênico/tratamento farmacológico , Desamino Arginina Vasopressina , Antidiuréticos/uso terapêutico , Estudos Retrospectivos , Administração Oral , Comprimidos/uso terapêutico , Arginina , SolubilidadeRESUMO
The urine concentration impairment responsible for hyposthenuria in sickle cell nephropathy is currently thought to be a consequence of renal medulla lesions, which lead to nephrogenic diabetes insipidus. The objective of the present study was to investigate the mechanism of hyposthenuria in patients with sickle cell anemia. We performed an observational study of patients with homozygous SS sickle cell anemia and data available on the fasting plasma antidiuretic hormone (ADH) concentration. A total of 55 patients were analyzed. The fasting plasma ADH values ranged from 1.2 to 15.4 pg/mL, and 82% of the patients had elevated ADH values and low fasting urine osmolality (<505 mosmol/kgH2O). Plasma ADH was positively associated with plasma tonicity and natremia (P < 0.001). None of the patients experienced polyuria and fasting free water clearance was negative in all cases, thus, ruling out nephrogenic diabetes insipidus. The tertile groups did not differ with regard to fasting urine osmolality, plasma renin level, mGFR, or several hemolysis biomarkers. The negative fasting free water clearance in all cases and the strong association between 24-h osmolal clearance and 24-h diuresis favors the diagnosis of osmotic diuresis due to an impaired medullary gradient, rather than lesions to collecting tubule.NEW & NOTEWORTHY The urine concentration impairment in sickle cell anemia is an osmotic diuresis related to an impaired renal medullary gradient leading to an ADH plateau effect. The fasting plasma ADH was high in the context of a basic state of close-to-maximal urine concentration probably driven by short nephrons maintaining a cortex-outer medullary gradient (about 400 milliosmoles). The patients had a low daily osmoles intake without evidence of thirst dysregulation so no one experienced polyuria.
Assuntos
Anemia Falciforme , Diabetes Insípido Nefrogênico , Diabetes Insípido , Diabetes Mellitus , Humanos , Poliúria , Diurese , Concentração Osmolar , Antidiuréticos , ÁguaRESUMO
Maintenance of renal function and fluid transport are essential for vertebrates and invertebrates to adapt to physiological and pathological challenges. Human patients with malignant tumours frequently develop detrimental renal dysfunction and oliguria, and previous studies suggest the involvement of chemotherapeutic toxicity and tumour-associated inflammation1,2. However, how tumours might directly modulate renal functions remains largely unclear. Here, using conserved tumour models in Drosophila melanogaster3, we characterized isoform F of ion transport peptide (ITPF) as a fly antidiuretic hormone that is secreted by a subset of yki3SA gut tumour cells, impairs renal function and causes severe abdomen bloating and fluid accumulation. Mechanistically, tumour-derived ITPF targets the G-protein-coupled receptor TkR99D in stellate cells of Malpighian tubules-an excretory organ that is equivalent to renal tubules4-to activate nitric oxide synthase-cGMP signalling and inhibit fluid excretion. We further uncovered antidiuretic functions of mammalian neurokinin 3 receptor (NK3R), the homologue of fly TkR99D, as pharmaceutical blockade of NK3R efficiently alleviates renal tubular dysfunction in mice bearing different malignant tumours. Together, our results demonstrate a novel antidiuretic pathway mediating tumour-renal crosstalk across species and offer therapeutic opportunities for the treatment of cancer-associated renal dysfunction.
Assuntos
Antidiuréticos , Nefropatias , Neoplasias , Neuropeptídeos , Receptores da Neurocinina-3 , Animais , Humanos , Camundongos , Antidiuréticos/metabolismo , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Nefropatias/complicações , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Túbulos de Malpighi/citologia , Túbulos de Malpighi/metabolismo , Neoplasias/complicações , Neoplasias/metabolismo , Óxido Nítrico Sintase/metabolismo , Receptores da Neurocinina-3/antagonistas & inibidores , Receptores da Neurocinina-3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Arginina Vasopressina/metabolismo , Proteínas de Drosophila/metabolismo , Neuropeptídeos/metabolismoRESUMO
BACKGROUND/AIM: Effect predictors of desmopressin for nocturia associated with nocturnal polyuria are understudied. Herein, we investigated the effects of desmopressin on sleep and patient quality of life. We defined cases in which administration of desmopressin led to hours of undisturbed sleep (HUS) ≥3 hours as "marked response cases" and examined predictive factors of desmopressin treatment response. PATIENTS AND METHODS: Our study included 129 patients who were administered desmopressin 50 µg for nocturia associated with nocturnal polyuria at our hospital. Efficacy and safety of desmopressin were examined using bladder diaries, International Prostate Symptom Score, Overactive Bladder Symptom Score, Athens Insomnia Scale, Patient Global Impression of Improvement (PGI-I) score, physical examinations, blood tests, and body composition analyzers, and the predictors of desmopressin efficacy were investigated. RESULTS: Significant improvements in all endpoints were observed from the early stage onward after desmopressin treatment compared with before treatment. After treatment, HUS was significantly longer in patients with good PGI-I scores, which indicated patient satisfaction. Variation in nocturnal micturition frequency did not affect the improvement in patient satisfaction. Examination of cases defined as "marked response cases" showed that the mean night-time urine volume was an independent predictor of treatment response. CONCLUSION: Desmopressin can improve patients' quality of life and sleep by extending HUS. This suggests that desmopressin may be effective in patients with high mean night-time urine volumes based on their bladder diary.
Assuntos
Noctúria , Masculino , Humanos , Noctúria/etiologia , Noctúria/induzido quimicamente , Poliúria/complicações , Poliúria/tratamento farmacológico , Poliúria/induzido quimicamente , Desamino Arginina Vasopressina/efeitos adversos , Antidiuréticos/efeitos adversos , Qualidade de VidaRESUMO
Nocturnal enuresis is defined as intermittent urinary incontinence during sleep in children 5 years of age and older, occurring at least once a month for at least 3 months. In Japan, pediatricians who do not specialize in nocturnal enuresis have become more proactive in treating the condition since 2016, when the guidelines for treating it were revised for the first time in 12 years. For monosymptomatic nocturnal enuresis, the first step is lifestyle guidance, with a focus on the restriction of fluid intake at night; however, if lifestyle guidance does not decrease the frequency of nocturnal enuresis, aggressive treatment should be added. The first choice of aggressive treatment is oral desmopressin, an antidiuretic hormone preparation, or alarm therapy. However, there remain patients whose wet nights do not decrease with oral desmopressin or alarm therapy. In such cases, it is necessary to reconfirm the method of desmopressin administration and check for factors that may decrease the efficacy of desmopressin. If alarm therapy does not increase the number of dry nights, it is possible that the patient is fundamentally unsuitable for alarm therapy. If dry nights do not increase with oral desmopressin or alarm therapy, the next treatment strategy should be considered immediately to keep the patient motivated for treatment.
Assuntos
Desamino Arginina Vasopressina , Enurese Noturna , Enurese Noturna/diagnóstico , Enurese Noturna/tratamento farmacológico , Humanos , Antagonistas Colinérgicos , Agonistas de Receptores Adrenérgicos beta 3 , Desamino Arginina Vasopressina/uso terapêutico , Antidiuréticos/uso terapêuticoRESUMO
OBJECTIVE: There is no consistent opinion on the optimal initial dose of desmopressin for patients with nocturnal polyuria. Over a period of 12 weeks, we investigated the safety and efficacy of an initial dose of 50 µg of desmopressin for elderly men. METHODS: Eighty patients (mean age: 78.8 years) were started on an initial dose of 50 µg of desmopressin for nocturia associated with nocturnal polyuria. Safety and efficacy were evaluated after 1, 4, and 12 weeks using a frequency-volume chart, Athens Insomnia Scale, Patient Global Impression of Improvement scale, physical examination, blood tests, and a body composition analyzer. RESULTS: Along with reduction in the frequency and volume of night-time urination, improvements in hours of undisturbed sleep, nocturnal polyuria index, and International Prostate Symptom Score, and Overactive Bladder Symptom Scores on quality of life measures were also observed. Hyponatremia was observed in 15 patients (18.7%). However, only 5.0% of patients had hyponatremia after the dose was reduced to 25 µg, and the continuation rate at 12 weeks was high at 87.5%. Age and other physical factors, such as body mass index, body water content, body fat mass, and muscle mass were not significant predictors of adverse events. CONCLUSIONS: Our study suggests that an initial dose of 50 µg is more effective than a uniformly minimum dose based on factors such as age and physique. Furthermore, a high continuation rate can be achieved by appropriately reducing the dose, if adverse events occur.
Assuntos
Hiponatremia , Noctúria , Masculino , Humanos , Idoso , Noctúria/tratamento farmacológico , Noctúria/diagnóstico , Desamino Arginina Vasopressina/efeitos adversos , Poliúria/induzido quimicamente , Poliúria/tratamento farmacológico , Poliúria/complicações , Antidiuréticos/efeitos adversos , Hiponatremia/complicações , Qualidade de Vida , População do Leste AsiáticoRESUMO
BACKGROUND/AIM: Nocturia is defined as the symptom that an individual has to disrupt their sleep at night, for one or several times, in order to void. Nocturia is a bothersome event that markedly reduces a patient's quality of life. The aim of the study was to elucidate which drugs, prescribed to reduce nocturia, show real-world efficacy in patients with bladder storage symptoms. PATIENTS AND METHODS: One hundred consecutive patients who visited the Fukuoka University Medical Center were evaluated between May and July 2022. Anticholinergic drugs, ß3 adrenoceptor agonists, α1 blockers, desmopressin, and other medicines were prescribed for relieving nocturia. Desmopressin was used as second-line treatment of nocturia only in males with nocturnal polyuria. The association between each drug and actual decrease in nocturia was investigated using multivariate analysis. RESULTS: The number of nocturia episodes was reduced in patients using anticholinergic drugs, ß3 adrenoceptor agonists, and desmopressin (-1.4±0.9, -1.3±0.9, -2.0 ±0.8 episodes/night, respectively). Multivariate analysis for the entire cohort showed that anticholinergic drugs and ß3 adrenoceptor agonists were associated with significantly decreased nocturia episodes (p=0.01 and p=0.04, respectively). In males, only desmopressin was associated with a significant decrease in nocturia (p=0.03), and combination therapy significantly decreased the number of nocturia episodes compared to monotherapy (p=0.001). CONCLUSION: In a real-world clinical setting, anticholinergic drugs and ß3 adrenoceptor agonists were similarly effective in reducing nocturia. Administration of desmopressin combined with anticholinergic drugs and/or ß3 adrenoceptor agonists is the most effective method for reducing nocturia in male patients with both storage symptoms and nocturnal polyuria.
Assuntos
Noctúria , Bexiga Urinária , Humanos , Masculino , Antidiuréticos/uso terapêutico , Antidiuréticos/efeitos adversos , Antagonistas Colinérgicos/uso terapêutico , Antagonistas Colinérgicos/farmacologia , Desamino Arginina Vasopressina/uso terapêutico , Noctúria/tratamento farmacológico , Poliúria/induzido quimicamente , Poliúria/complicações , Poliúria/tratamento farmacológico , Qualidade de Vida , Receptores Adrenérgicos/uso terapêutico , Bexiga Urinária/patologiaRESUMO
We examined urine excretion during primary acute sympathetic activation (PASA) in anesthetized Wistar-Kyoto rats. Since arterial pressure (AP) changes with sympathetic nerve activity (SNA) during PASA, urine excretion reflects a neurally mediated antidiuretic effect combined with an effect of pressure diuresis. We hypothesized that preventing AP changes under PASA would enable the direct estimation of the neurally mediated antidiuretic effect alone. We changed the isolated carotid sinus pressure stepwise from 60 to 180 mmHg and compared the relationship of normalized urine flow (nUF, urine flow normalized by body weight) versus SNA between conditions allowing and preventing baroreflex-mediated changes in the mean AP. The slope of the SNA-nUF relationship was [Formula: see text]nUFvar = 0.444 ± 0.074 µL·min-1·kg-1·%-1 when the mean AP was variable, whereas it was [Formula: see text]nUFfix = -0.143 ± 0.032 µL·min-1·kg-1·%-1 when the mean AP was fixed at 100 mmHg (n = 7 rats). The slope associated with the effect of pressure diuresis alone, calculated as [Formula: see text]nUFvar - [Formula: see text]nUFfix, was 0.586 ± 0.105 µL·min-1·kg-1·%-1. Hence, the potency of the neurally mediated antidiuretic effect |[Formula: see text]nUFfix|/([Formula: see text]nUFvar - [Formula: see text]nUFfix) was 0.235 ± 0.014 relative to the effect of pressure diuresis under PASA. Our findings would aid an integrative understanding of the effects of renal hemodynamic and sympathetic modulations on urine output function.
Assuntos
Antidiuréticos , Pressão Arterial , Ratos , Animais , Pressão Sanguínea/fisiologia , Antidiuréticos/farmacologia , Ratos Endogâmicos WKY , Sistema Nervoso Simpático/fisiologia , Diurese , Barorreflexo/fisiologiaRESUMO
Background: Enuresis, defined as involuntary nocturnal urination without any underlying organic disorder in a child expected to control urination, poses a common problem. This study evaluated the effectiveness of Tolterodine and Oxybutynin in children presenting with primary desmopressin-resistant enuresis. Materials and Methods: A randomized clinical trial was undertaken involving 68 participants aged between 5 and 16 years, all suffering from primary enuresis. These patients were randomly assigned to one of two treatment groups for a three-month period: Group 1, treated with Oxybutynin and Desmopressin, and Group 2, treated with Tolterodine and Desmopressin. Data on demographics, clinical and laboratory findings, and subjective responses to treatment were gathered. The response was measured based on the frequency of wetting incidents per night and week and compared with pre-treatment data. Results: Patients were divided into two groups (30 patients in Group 1 and 38 patients in Group 2). The mean age of the patients was 88.97±27.09 months. In the first treatment group, 6 out of 30 patients (20%) experienced a complete treatment response, as did 5 out of 38 patients (13.2%) in the second treatment group. This difference between the groups was not statistically significant. Seven patients (23%) in the Oxybutynin group and 13 patients (34%) in the Tolterodine group reported a lack of response to treatment, a difference that also lacked statistical significance. Conclusion: For patients resistant to Desmopressin, the addition of anticholinergic drugs elicited a significant response in over half of the patients. However, no benefit was observed in using either Oxybutynin or Tolterodine in the treatment of Desmopressin-resistant enuresis.
Assuntos
Desamino Arginina Vasopressina , Ácidos Mandélicos , Tartarato de Tolterodina , Humanos , Tartarato de Tolterodina/uso terapêutico , Criança , Ácidos Mandélicos/uso terapêutico , Masculino , Feminino , Desamino Arginina Vasopressina/uso terapêutico , Adolescente , Resultado do Tratamento , Pré-Escolar , Enurese Noturna/tratamento farmacológico , Antagonistas Muscarínicos/uso terapêutico , Antidiuréticos/uso terapêutico , Agentes Urológicos/uso terapêutico , Enurese/tratamento farmacológico , Resistência a MedicamentosRESUMO
Discovering new drug candidates with high efficacy and few side effects is a major challenge in new drug development. The two evolutionarily related peptides oxytocin (OXT) and arginine vasopressin (AVP) are known to be associated with a variety of physiological and psychological processes via the association of OXT with three types of AVP receptors. Over decades, many synthetic analogs of these peptides have been designed and tested for therapeutic applications; however, only a few studies of their natural analogs have been performed. In this study, we investigated the bioactivity and usefulness of two natural OXT/AVP analogs that originate from the marine invertebrate Octopus vulgaris, named octopressin (OTP) and cephalotocin (CPT). By measuring the intracellular Ca2+ or cyclic AMP increase in each OXT/AVP receptor subtype-overexpressing cell, we found that CPT, but not OTP, acts as a selective agonist of human AVP type 1b and 2 receptors. This behavior is reminiscent of desmopressin, the most widely prescribed antidiuretic drug in the world. Similar to the case for desmopressin, a single intravenous tail injection of CPT into Sprague-Dawley rats reduced urine output and increased urinary osmolality. In conclusion, we suggest that CPT has a significant antidiuretic effect and that CPT might be beneficial for treating urological conditions such as nocturia, enuresis, and diabetes insipidus.
Assuntos
Antidiuréticos , Octopodiformes , Ocitocina , Animais , Antidiuréticos/farmacologia , Arginina Vasopressina/análogos & derivados , Desamino Arginina Vasopressina/farmacologia , Felipressina/farmacologia , Octopodiformes/metabolismo , Ocitocina/análogos & derivados , Ocitocina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Vasopressinas/agonistas , Receptores de Vasopressinas/metabolismoRESUMO
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.
Assuntos
Tratamento Farmacológico da COVID-19 , Diabetes Insípido/prevenção & controle , SARS-CoV-2/efeitos dos fármacos , Vasopressinas/uso terapêutico , Animais , Antidiuréticos/química , Antidiuréticos/metabolismo , Antidiuréticos/uso terapêutico , COVID-19/epidemiologia , COVID-19/virologia , Desamino Arginina Vasopressina/química , Desamino Arginina Vasopressina/metabolismo , Desamino Arginina Vasopressina/uso terapêutico , Diabetes Insípido/metabolismo , Hemostáticos/química , Hemostáticos/metabolismo , Hemostáticos/uso terapêutico , Humanos , Lipressina/química , Lipressina/metabolismo , Lipressina/uso terapêutico , Estrutura Molecular , Ornipressina/química , Ornipressina/metabolismo , Ornipressina/uso terapêutico , Pandemias/prevenção & controle , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Terlipressina/química , Terlipressina/metabolismo , Terlipressina/uso terapêutico , Vasopressinas/química , Vasopressinas/metabolismoRESUMO
PURPOSE: This review aims to provide prescribing clinicians a deeper appreciation of desmopressin's clinical indications and formulation types, to better balance efficacy and safety through proper formulation selection. BACKGROUND: Since its discovery 50 years ago, desmopressin's antidiuretic properties have been used for central diabetes insipidus, primary monosymptomatic nocturnal enuresis and adult nocturnal polyuria, while its coagulant effects are useful for mild hemophilia A and von Willebrand Disease. During this time, newer formulations of desmopressin have also been introduced to the market raising questions on interchangeability, dose conversion and safety. The wide array of clinical indications and variable pharmacokinetic properties of different desmopressin preparations raises the possibility of medication error, especially the risk of hyponatraemia. METHODOLOGY: A narrative review to explore clinically relevant aspects of desmopressin therapy, synthesising information obtained from searches of published literature. RESULTS: We identified that the risk factors for developing hyponatremia include extremes of age, existing comorbidity, drug interaction, intranasal formulations and intercurrent illness. We describe the dose equivalence between all formulations to facilitate conversion. We highlight that in view of inter-subject variability, close monitoring is recommended when switching preparations. We found that paediatric data remains limited, leading to recent proposals for age- and weight-based dosing regimens. CONCLUSION: The risk of hyponatremia, albeit small, can be reduced by adhering to the indication-specific doses and taking steps to govern the safe prescription of the drug. Further paediatric clinical trials are awaited to expand the evidence base of childhood desmopressin therapy.