RESUMEN
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.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Diabetes Insípida/prevención & control , SARS-CoV-2/efectos de los fármacos , Vasopresinas/uso terapéutico , Animales , Fármacos Antidiuréticos/química , Fármacos Antidiuréticos/metabolismo , Fármacos Antidiuréticos/uso terapéutico , COVID-19/epidemiología , COVID-19/virología , Desamino Arginina Vasopresina/química , Desamino Arginina Vasopresina/metabolismo , Desamino Arginina Vasopresina/uso terapéutico , Diabetes Insípida/metabolismo , Hemostáticos/química , Hemostáticos/metabolismo , Hemostáticos/uso terapéutico , Humanos , Lipresina/química , Lipresina/metabolismo , Lipresina/uso terapéutico , Estructura Molecular , Ornipresina/química , Ornipresina/metabolismo , Ornipresina/uso terapéutico , Pandemias/prevención & control , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiología , Terlipresina/química , Terlipresina/metabolismo , Terlipresina/uso terapéutico , Vasopresinas/química , Vasopresinas/metabolismoRESUMEN
Arginine-vasopressin (AVP) and lysine-vasopressin (LVP) were analyzed by reversed-phase liquid chromatography/mass spectrometry (LC-MS) using Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry (MS) electrospray ionization (ESI) in the positive ion mode. LVP and AVP exhibited the protonated adduct [M+H](+) as the predominant ion at m/z 1056.43965 and at m/z 1084.44561, respectively. Infrared multiphoton dissociation (IRMPD), using a CO(2) laser source at a wavelength of 10.6 µm, was applied to protonated vasopressin molecules. The IRMPD mass spectra presented abundant mass fragments essential for a complete structural information. Several fragment ions, shared between two target molecules, are discussed in detail. Some previously unpublished fragments were identified unambiguously utilizing the high resolution and accurate mass information provided by the FT-ICR mass spectrometer. The opening of the disulfide loop and the cleavage of the peptide bonds within the ring were observed even under low-energy fragmentation conditions. Coupling the high-performance FT-ICR mass spectrometer with IRMPD as a contemporary fragmentation technique proved to be very promising for the structural characterization of vasopressin.
Asunto(s)
Arginina Vasopresina/química , Ciclotrones , Lipresina/química , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrofotometría Infrarroja/métodos , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Lipresina/análisisRESUMEN
This study investigated the outcomes of living donor liver transplantation (LDLT) for patients with preoperative type 1 hepatorenal syndrome (HRS) and acute hepatic decompensation. Prospectively collected data for 104 patients who had fulminant hepatic failure, acute decompensation of cirrhosis, or an acute flare of chronic hepatitis B were analyzed. Thirty-three patients (31.7%) had HRS (the HRS group), and 71 patients (68.3%) did not (the non-HRS group). The median follow-up period was 60 months. The HRS group had significantly more preoperative intensive care unit (ICU) admissions (84.8% versus 60.6%, P = 0.01), worse preoperative blood test results (creatinine, 248 versus 88 µmol/L, P < 0.001; total bilirubin, 630 versus 555 µmol/L, P = 0.001), more hemodialysis (48.5% versus 0%, P < 0.001), more blood transfusions (9 versus 4 U, P < 0.001), longer postoperative ICU stays (8 versus 4 days, P < 0.001), worse postoperative blood test results (creatinine at 1 year, 108 versus 96 µmol/L, P = 0.006), and poorer overall survival (P < 0.001). In a multivariate analysis, only HRS was associated with poorer overall survival (hazard ratio = 8.592, 95% confidence interval = 1.782-41.431, P = 0.007). In conclusion, HRS patients had worse postoperative renal function and overall survival than non-HRS patients. However, their 5-year overall survival rate was still nearly 80%, which is satisfactory. Therefore, LDLT can be considered for patients who have acute hepatic decompensation with or without HRS.
Asunto(s)
Síndrome Hepatorrenal/terapia , Hepatopatías/terapia , Trasplante de Hígado/métodos , Donadores Vivos , Adulto , Albúminas/metabolismo , Comorbilidad , Femenino , Estudios de Seguimiento , Síndrome Hepatorrenal/fisiopatología , Humanos , Inmunosupresores/uso terapéutico , Hepatopatías/fisiopatología , Lipresina/análogos & derivados , Lipresina/química , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Diálisis Renal , Factores de Riesgo , Terlipresina , Resultado del TratamientoRESUMEN
Arginine vasopressin (AVP) and its synthetic, long-acting analog terlipressin (TP) are potent alternative vasoconstrictors in the treatment of septic patients with catecholamine-refractive vasodilatatory shock. The results from one large randomized clinical trial suggest that AVP plus norepinephrine (NE) infusion is as safe and effective as treatment with NE alone in patients with septic shock. Because the desired effects of vasopressin analogs are basically related to their vasopressinergic effects via the V1a receptor, more selective V1 agonists, such as TP, may be more potent in reversing sepsis-related arterial hypotension. In this regard, recent evidence from small-scale studies suggests that continuous low-dose infusion rather than intermittent bolus injection of TP is associated with fewer side effects, such as depression of cardiac output and rebound arterial hypotension. However, because clinical data on the administration of TP in patients with sepsis are limited, it should not currently be used beyond the scope of controlled trials. The optimal time point for the initiation of therapy with vasopressin analogs has yet to be determined. While AVP and TP are commonly used as last-resort therapies in severe septic shock, some evidence supports the initiation of treatment in a less severe state of the disease.
Asunto(s)
Arginina Vasopresina/uso terapéutico , Hipotensión/tratamiento farmacológico , Lipresina/análogos & derivados , Sepsis/fisiopatología , Vasoconstrictores/uso terapéutico , Corticoesteroides/efectos adversos , Corticoesteroides/farmacología , Corticoesteroides/uso terapéutico , Animales , Arginina Vasopresina/administración & dosificación , Arginina Vasopresina/efectos adversos , Arginina Vasopresina/química , Arginina Vasopresina/farmacología , Catecolaminas/efectos adversos , Catecolaminas/farmacología , Catecolaminas/uso terapéutico , Vías de Administración de Medicamentos , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Quimioterapia Combinada , Humanos , Hipotensión/etiología , Isquemia/inducido químicamente , Lipresina/administración & dosificación , Lipresina/efectos adversos , Lipresina/química , Lipresina/farmacología , Lipresina/uso terapéutico , Estructura Molecular , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Vasopresinas/agonistas , Receptores de Vasopresinas/fisiología , Sepsis/complicaciones , Choque Séptico/complicaciones , Choque Séptico/fisiopatología , Terlipresina , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/administración & dosificación , Vasoconstrictores/efectos adversosRESUMEN
Porous and rigid methacrylic Synbeads were optimized and applied efficiently to the solid phase peptide synthesis with the objective of improving significantly volumetric yields (0.33 mol/L calculated on the basis of maximum chemical accessibility, i.e. the maximum number of functional groups that can be acylated by FmocCl) as compared to swelling commercial polymers (from 0.06 to 0.12 mol/L). The effects of the density of functional groups and spacer length were investigated obtaining a chemical accessibility of the functional groups up to 1 mmol/g(dry). High resolution magic angle spinning (HR-MAS) was exploited to evidence the presence of "solution-like" flexible linkers anchored on the rigid methacrylic backbone of Synbeads and to study the degree of functionalization by the Wang linker. To demonstrate the efficiency of the optimized Synbeads, the peptides Somatostatin and Terlipressin were synthesized. In the case of Somatostatin, final synthetic yields of 45 and 60% were achieved by following the HCTU/DIPEA and DIC/HOBt routes respectively, with the HPLC purity always higher than 83%. In the case of Terlipressin, the synthesis was carried out in parallel on Synbeads and also on TentaGel, ChemMatrix, and PS-DVB for comparison (DIC/HOBt route). The profiles describing the synthetic efficiency demonstrated that Synbeads leads to synthetic efficiency (86%) comparable to PS-DVB (96%) or ChemMatrix (84%). In order to gain a more precise picture of chemical and morphological features of Synbeads, their matrix was also characterized by exploiting innovative approaches based on FTIR microspectroscopy with a conventional source and with synchrotron radiation. A uniform distribution of the functional groups was evidenced through a detailed chemical mapping.
Asunto(s)
Lipresina/análogos & derivados , Espectroscopía de Resonancia Magnética/métodos , Metacrilatos/química , Polímeros/química , Somatostatina/síntesis química , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Cromatografía Líquida de Alta Presión , Lipresina/química , Microscopía Electrónica de Rastreo , TerlipresinaRESUMEN
OBJECTIVE: To review and assess available literature on chemistry, pharmacology, pharmacodynamics, pharmacokinetics, clinical studies, adverse events, drug interactions, and dosing and administration of terlipressin in septic shock. DATA SOURCES: A literature search of MEDLINE (1966-September 2006), International Pharmaceutical Abstracts (1970-September 2006), and Cochrane database (third quarter 2006) was conducted, using key terms of terlipressin, lypressin, triglycyl-lysine vasopressin, hemodynamic support, septic shock, vasopressor, and V1 receptor agonist. Bibliographies of relevant articles were reviewed for additional references. STUDY SELECTION AND DATA EXTRACTION: Available English-language literature, including abstracts, animal studies, preclinical studies, clinical trials, and review articles, were examined. DATA SYNTHESIS: Because of potentially favorable pharmacokinetics versus vasopressin and limited availability of vasopressin in some countries, the effects of terlipressin, a vasopressin analog, have been studied recently for the treatment of septic shock. When administered as a 1-2 mg intravenous dose in patients with septic shock, terlipressin increases mean arterial pressure, urine output, systemic vascular resistance index, pulmonary vascular resistance index, and left and right ventricular stroke work index while decreasing heart rate, cardiac output, lactate, and oxygen delivery and consumption index. It is unclear whether lower doses of terlipressin would produce a similar vasopressor response with fewer cardiopulmonary effects and whether the effects of the drug on oxygen transport indices are detrimental. CONCLUSIONS: Terlipressin is a promising investigational medication for treatment of septic shock. Small trials have shown terlipressin to have favorable effects on hemodynamics in patients with septic shock refractory to conventional vasopressor treatment. It should be used with extreme caution in patients with underlying cardiac or pulmonary dysfunction. Further studies are needed to verify safety, efficacy, and dosing of terlipressin in patients with septic shock, and its use cannot be recommended in lieu of vasopressin at this time.
Asunto(s)
Lipresina/análogos & derivados , Choque Séptico/tratamiento farmacológico , Vasopresinas/química , Vasopresinas/uso terapéutico , Animales , Humanos , Lipresina/química , Lipresina/farmacocinética , Lipresina/uso terapéutico , Receptores de Vasopresinas/metabolismo , Choque Séptico/sangre , Terlipresina , Vasopresinas/farmacocinéticaRESUMEN
The structures of des 1-6 bovine neurophysin-II in the unliganded state and as its complex with lysine vasopressin were determined crystallographically at resolutions of 2.4 A and 2.3 A, respectively. The structure of the protein component of the vasopressin complex was, with some local differences, similar to that determined earlier of the full-length protein complexed with oxytocin, but relatively large differences, probably intrinsic to the hormones, were observed between the structures of bound oxytocin and bound vasopressin at Gln 4. The structure of the unliganded protein is the first structure of an unliganded neurophysin. Comparison with the liganded state indicated significant binding-induced conformational changes that were the largest in the loop region comprising residues 50-58 and in the 7-10 region. A subtle binding-induced tightening of the subunit interface of the dimer also was shown, consistent with a role for interface changes in neurophysin allosteric mechanism, but one that is probably not predominant. Interface changes are suggested to be communicated from the binding site through the strands of beta-sheet that connect these two regions, in part with mediation by Gly 23. Comparison of unliganded and liganded states additionally reveals that the binding site for the hormone alpha-amino group is largely preformed and accessible in the unliganded state, suggesting that it represents the initial site of hormone protein recognition. The potential molecular basis for its thermodynamic contribution to binding is discussed.
Asunto(s)
Neurofisinas/química , Neurofisinas/metabolismo , Vasopresinas/química , Vasopresinas/metabolismo , Regulación Alostérica , Animales , Sitios de Unión , Bovinos , Cristalografía por Rayos X , Enlace de Hidrógeno , Ligandos , Lipresina/química , Lipresina/metabolismo , Modelos Moleculares , Oxitocina/química , Oxitocina/metabolismo , Unión Proteica , Pliegue de Proteína , Estructura Terciaria de ProteínaAsunto(s)
Antihipertensivos/uso terapéutico , Várices Esofágicas y Gástricas/tratamiento farmacológico , Hemorragia Gastrointestinal/tratamiento farmacológico , Lipresina/análogos & derivados , Vasoconstrictores/uso terapéutico , Antihipertensivos/química , Humanos , Lipresina/química , Lipresina/uso terapéutico , Terlipresina , Vasoconstrictores/químicaAsunto(s)
4-Cloro-7-nitrobenzofurazano/análogos & derivados , Felipresina/análisis , Análisis de Inyección de Flujo/métodos , Lipresina/análisis , Oligopéptidos/análisis , 4-Cloro-7-nitrobenzofurazano/química , Acetonitrilos/química , Felipresina/química , Indicadores y Reactivos/química , Lipresina/química , Espectrometría de Fluorescencia , TemperaturaRESUMEN
Copper(II) complexes of oxytocin, 4-Glu-oxytocin, 5-Asp-oxytocin, and GlyGlyGly-Lys8-vasopressin were studied by potentiometric, EPR, and UV-visible spectroscopic methods. The formation of 4N-coordinated complexes was characteristic of all ligands. This type of coordination is especially favored for oxytocin due to the specific conformation of the ring coupled by the disulfide bridge. The coordination of the gamma-carboxylate group of 4-Glu-oxytocin and a disulfide sulfur atom of GlyGlyGly-Lys8-vasopressin was reported to occur in the 2N-complexes over medium pH range.
Asunto(s)
Disulfuros/química , Hormonas/química , Lipresina/análogos & derivados , Oxitocina/análogos & derivados , Potenciometría , Espectrofotometría/métodos , Secuencia de Aminoácidos , Espectroscopía de Resonancia por Spin del Electrón , Lipresina/química , Datos de Secuencia Molecular , TerlipresinaRESUMEN
Lysine vasopressin (LVP) readily reacts with reducing saccharides both in lyophilized preparations and in aqueous solution. Incubation of LVP with, for example, lactose over a pH range of 3.0-8.5 in phosphate buffer or simply in water, gives rise to a number of reaction products, some of which form rapidly (in a matter of hours) even in the frozen state. Reaction mixtures were analysed by reversed-phase HPLC and the structures of the products were deduced from the amino-acid composition of isolated components, by comparison with product profiles obtained with analogues under similar conditions and by FAB mass-spectral analysis of derivatives isolated after reduction with cyanoborohydride. The primary products arise from the formation of Schiff's bases at one or both of the two amino functions. The alpha-amino group of the N-terminal cystine is considerably more reactive than is the epsilon-amino group of lysine and it is the N-terminal adduct which rapidly forms even at -20 degrees C. It is concluded that caution must be shown in using reducing sugars in formulations containing peptides and proteins, particularly the vasopressins and oxytocin.
Asunto(s)
Lactosa/química , Lipresina/química , Secuencia de Aminoácidos , Cromatografía Líquida de Alta Presión , Liofilización , Glicosilación , Lactosa/análisis , Datos de Secuencia Molecular , TemperaturaRESUMEN
Several neuropeptides are suspected to act on the control of hydric balance in leeches. One of these peptides, a peptide immunoreactive to an antibody against oxytocin, was previously characterized from the central nervous system of the leech Erpobdella octoculata [Salzet, M., Wattez, C., Verger-Bocquet, M., Beauvillain, J.-C. & Malecha, J. (1993) Brain Res. 601, 173-184]. This paper reports the isolation from the central nervous system of E. octoculata of another peptide of the oxytocin/vasopressin family; a lysine-vasopressin-like molecule. Its purification was performed by reverse-phase high-performance liquid chromatography combined with both dot immunobinding assay and enzyme-linked immunosorbent assay for lysine-vasopressin. The amino acid sequence was established by Edman degradation and confirmed by electrospray-mass-spectrometry measurement. The nonapeptide obtained corresponded to the lysine-conopressin previously isolated from the venom of the mollusc Conus geographus [Cruz, L. L., de Santos, V., Zafaralla, G. C., Ramilo, C. A., Zeikus, R., Gray, W. R. & Olivera, B. M. (1987) J. Biol. Chem. 262, 15821-15824]. In leeches, synthetic lysine-conopressin exerts a diuretic effect which can be compared to that of the arginine-vasopressin-like peptide isolated in the Insect Locusta migratoria [Proux, J., Miller, C. A., Li, J. P., Carney, R. L., Girardie, A., Delaage, M. & Schooley, D. A. (1987) Biochem. Biophys. Res. Commun. 149, 180-186].
Asunto(s)
Sistema Nervioso Central/química , Sanguijuelas/química , Oxitocina/análogos & derivados , Secuencia de Aminoácidos , Animales , Cromatografía Líquida de Alta Presión , Ensayo de Inmunoadsorción Enzimática , Lipresina/química , Espectrometría de Masas , Datos de Secuencia Molecular , Oligopéptidos/química , Oxitocina/química , Oxitocina/aislamiento & purificación , Oxitocina/metabolismoRESUMEN
Purification of 125I-labelled lysine-vasopressin has been achieved by affinity chromatography on a Sepharose 4 B conjugate of porcine neurophysins. This affinity absorbent did not retain halogenated hormone, while native lysine-vasopressin was bound on the solid support. The specific activity of purified iodinated lysine-vasopressin was 1700-1800 Ci/g, corresponding to one iodine atom per mole. By comparison with an unpurified tracer, a five times increase in the minimum detectable dose was obtained in the vasopressin radioimmunoassay.