遗传性肾性尿崩症的药物治疗

遗传性肾性尿崩症由精氨酸加压素受体2 (AVPR2)或水通道蛋白-2(AQP2)基因突变引起.目前临床治疗主要是改善多饮、多尿的症状.随着对发病机制研究的不断深入,新型药物如AVPR2激动剂和拮抗剂、磷酸二酯酶抑制剂、他汀类、前列腺素E受体激动剂等,通过改善突变的AVPR2/AQP2在细胞内的合成、修饰、表达等达到治疗的目的.     

血管加压素受体拮抗剂临床研究的现状及展望

传统治疗等容性或高容量性低钠血症的方法包括限水、应用高渗盐水及去甲金霉素等,但均有明显的副作用,导致其临床应用受限.血管加压素受体拮抗剂(VRAs)主要通过阻断过度产生的(精氨酸加压素)AVP,使净水(非溶质水)排出增加,达到升高血浆渗透压的作用已被美国食品药品管理局(FDA)批准用于治疗等容性低钠血症.对此类药物的进一步研究发现VRAs还可用于治疗由于AVP受体变异导致的肾源性糖尿病(NDI),甚至可能延缓多囊肾的进展.本文对于目前国内外非肽类VRAs药物的研究情况进行综述,并进一步探讨其潜在的临床使用价值.     

支气管哮喘药物治疗进展

吸入性肾上腺糖皮质激素(ICS)是目前治疗支气管哮喘(简称哮喘)最有效的药物,已成为哮喘长期治疗的一线药物。单纯吸入激素或吸入激素联合长效肾上腺素β2受体(β2受体)激动剂可使大多数哮喘患者得到良好控制,但有部分哮喘患者即使口服激素仍反复发作,部分患者停用激素后易复发。且长期使用大剂量ICS,全身不良反应明显。所以发     

比索洛尔、美托洛尔和普萘洛尔治疗甲状腺功能亢进性心动过速疗效比较

甲状腺功能亢进(甲亢)患者90%以上有心动过速,严重者可并发心律失常和心力衰竭.常用的治疗药物是普萘洛尔;但普萘洛尔是非选择性β受体阻滞剂,对β2受体的阻滞限制了部分患者的使用.近些年一些有针对性的选择性β1受体阻滞剂用于临床,但不同的药物作用机制不完全相同,对控制甲亢性心动过速的疗效和对甲状腺激素的影响报道不一.本研究比较了目前临床常用的比索洛尔、普萘洛尔和美托洛尔治疗甲亢性心动过速的疗效,对外周血游离T4(FT4)转换为游离T3(FT3)是否有影响进行了比较和分析.     

冠状动脉狭窄后再通的治疗策略及临床管理经验

对冠状动脉内血栓、斑块破裂等多种原因导致冠状动脉的狭窄或部分/完全性阻塞,可以使用抗血小板(阿司匹林、二磷酸腺苷受体阻滞剂)和非肠道抗凝剂进行治疗。此外,临床研究发现,糖蛋白ⅡB/Ⅲa受体抑制剂(GPI)和血管扩张药物对于改善病灶部位血栓以及心外膜和心肌灌注也十分有益。这些药物可以明显改善冠状动脉内的血流缓慢和(或)经皮冠状动脉介入(PCI)治疗后无复流的情况。本文对目前临床上使用的冠状动脉狭窄后再通的治疗策略及临床管理经验进行总结归纳,并进一步对未来临床的药物使用及治疗方案等进行深入探讨。     

多巴胺受体激动剂治疗中晚期帕金森病的临床研究

帕金森病(PD)是以运动减少、震颤和肌强直为主要表现的一种神经变性疾病,晚期致残率较高。左旋多巴替代治疗一直是基本的治疗药物。近年研究表明多巴胺(DA)受体激动剂不但能缓解其临床症状,还可以克服左旋多巴的不足,且具有神经保护作用[1],主张将DA受体激动剂用于早发(<50岁发病)的PD患者或者与左旋多巴制剂联合应用治疗中晚期PD[2]。本研究观察了34例应用DA受体激动剂(吡贝地尔缓释剂,商品名:泰舒达)或复方左旋多巴制剂(多巴丝肼,商品名:美多芭)治疗的中晚期PD患者,初步探索DA受体激动剂治疗中晚期PD的临床疗效。1资料与方法1.1病…     

慢性阻塞性肺疾病和肺内受体相关药理学意义

当前治疗慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)的绝大多数药物作用于气道内细胞所表达的受体.因为吸入治疗可以传送药物到关键靶位细胞,并且全身副作用较小,所以吸入治疗成为当前治疗COPD最有前途的治疗方式.β2肾上腺素受体激动剂和抗胆碱能药都靶向到大小气道平滑肌上自主神经受体,发挥支气管扩张作用,同时β2肾上腺素受体激动剂还可作用到炎症细胞等其他靶位细胞上的受体而发挥抗炎作用.糖皮质激素受体分布广泛,吸入治疗使用普遍.肺部还有许多其他受体靶位,包括趋化因子受体和孤儿受体等,相应药物正在临床开发.     

慢性心力衰竭的心脏再同步化治疗

随着血管紧张素转化酶抑制剂(或血管紧张素受体拮抗剂)、β受体阻滞剂、醛固酮拮抗剂在临床上广泛应用,慢性心力衰竭(CHF)治疗取得了很大的进展,然而有相当数量的患者药物治疗仍不能阻止心力衰竭的进行性加重.     

心律失常上游药物的治疗研究进展

心律失常是临床上最常见的疾病之一,是当今心脏疾病领域中的一大难题.无论是药物治疗还是非药物治疗,都有很多问题需要解决.近年来研究显示血管紧张素转换酶抑制剂(ACEI)、血管紧张素受体阻滞剂(ARB)、醛固酮受体拮抗剂、他汀类药物、不饱和脂肪酸等心律失常上游药物(upstream medical agents)均具有抗心律失常作用.     

老年心动过速心肌病17例临床分析

心动过速心肌病( TCM)系长期慢性心动过速导致不规则或过高心室率,引起心脏扩大并最终引发心力衰竭的临床综合征,但在心率或节律得到控制后,心功能可以部分或全部恢复.TCM最大特征就是心律失常治愈或控制后心功能可以改善.因此,尽早识别和治疗具有极大的临床价值.临床有效的治疗方法主要有药物和射频消融(RFCA)两种,药物治疗不能根治,长期应用还会导致严重的副作用,包括致心律失常、负性肌力作用等.随着RFCA术的发展,其已成为治疗快速性心律失常的首选方法.本研究旨在对本院收治的17例TCM患者病因、临床表现、治疗及预后等临床特点进行回顾性分析.     

Intracellular activation of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus by nonpeptide agonists

Binding of the peptide hormone vasopressin to its type-2 receptor (V2R) in kidney triggers a cAMP-mediated translocation of Aquaporin-2 water channels to the apical membrane, resulting in water reabsorption and thereby preventing dehydration. Mutations in the V2R gene lead to Nephrogenic Diabetes Insipidus (NDI), a disorder in which this process is disturbed, because the encoded, often intrinsically functional mutant V2 receptors are misfolded and retained in the endoplasmic reticulum (ER). Since plasma membrane expression is thought to be essential for V2R activation, cell permeable V2R antagonists have been used to induce maturation and rescue cell surface expression of V2R mutants, after which they need to be displaced by vasopressin for activation. Here, however, we show that 3 novel nonpeptide V2R agonists, but not vasopressin, activate NDI-causing V2R mutants at their intracellular location, without changing their maturation and at a sufficient level to induce the translocation of aquaporin-2 to the apical membrane. Moreover, in contrast to plasma membrane V2R, degradation of intracellular V2R mutants is not increased by their activation. Our data reveal that G protein-coupled receptors (GPCRs) normally active at the plasma membrane can be activated intracellularly and that intracellular activation does not induce their degradation; the data also indicate that nonpeptide agonists constitute highly promising therapeutics for diseases caused by misfolded GPCRs in general, and NDI in particular.     

Physiopathology and diagnosis of nephrogenic diabetes insipidus

Nephrogenic diabetes insipidus (NDI) is caused by an improper response of the kidney to the antidiuretic hormone arginine vasopressin (AVP), leading to a decreased ability to concentrate urine which results in polyuria and polydipsia. The clinical diagnosis of NDI relies on demonstration of subnormal ability to concentrate urine despite the presence of AVP. NDI is most commonly acquired, secondary to kidney disorders, electrolyte imbalance and various drugs. Congenital forms of NDI are rare, and most commonly inherited in a X-linked manner with mutations of the AVP receptor type 2 (AVPR2). Mutations of the water channel aquaporin-2 (AQP2) can be detected in autosomal recessive or dominant forms of NDI. Management of NDI should focus on free access to drinking water and reduction of polyuria.     

The property of a novel v2 receptor mutant in a patient with nephrogenic diabetes insipidus

Nephrogenic diabetes insipidus (NDI) is characterized by resistance of the kidneys to the action of arginine vasopressin (AVP); X-linked recessive NDI is caused by an inactivating mutation of the vasopressin type-2 (V2) receptor. Several missense mutations in the first or second extracellular loop of the V2 receptor have been reported, and some of these mutant receptors were confirmed to have reduced affinities for ligand binding. We detected a novel V2 receptor gene mutation, a substitution of cysteine for arginine-104 (R104C) located in the first extracellular loop of the V2 receptor, in a patient with congenital NDI. Functional analysis by transient expression studies with COS-7 cells showed binding capacity of R104C mutant diminished as 10% of wild type, but binding affinity was strong rather than wild type. In the result of AVP stimulation studies, maximum cAMP accumulation of R104C decreased as 50% of wild type. On the other hand, a designed mutant receptor, substituted serine for arginine-104 as a model of modified R104C mutant receptor removed the influence of the sulfhydryl group in cysteine-104, recovered binding capacity up to 50% of wild type and maximum cAMP accumulation as 82% of wild type. Our study demonstrated that the R104C mutation of the V2 receptor was a cause of NDI. The mechanism of renal resistance to AVP was the reduction of ligand binding, and adenylyl cyclase activation depended on the V2 receptor. In addition, we confirmed that the sulfhydryl group of the cysteine-104 caused most part of R104C mutant receptor dysfunction.     

Identification and characterization of a novel X-linked AVPR2 mutation causing partial nephrogenic diabetes insipidus: a case report and review of the literature

X-linked nephrogenic diabetes insipidus (NDI) is a rare disease characterized by a malfunctioning renal response to the antidiuretic hormone arginine vasopressin (AVP) due to mutations in the AVPR2 gene. A limited number of mutations in the AVPR2 gene resulting in partial phenotype have been described so far. In this mini-review the retrospective analysis of 13 known AVPR2 mutations that have been previously shown in vitro to partially abolish AVPR2 function is described, along with a novel mutation diagnosed in a kindred with partial NDI. In the present study, a 14 year old male and his 73 year old maternal grandfather were diagnosed with partial NDI based on the clinical phenotype, the water deprivation test and the inadequate response to 1-desamino-8-d-arginine vasopressin (DDAVP) administration. Sequencing analysis of the AVPR2 gene revealed the novel missense mutation p.N317S (g.1417A > G) in both patients. This mutation was re-created by site directed mutagenesis in an AVPR2 cDNA expression vector and was functionally characterized, in terms of arginine vasopressin (AVP) and DDAVP response. AVPR2 activity of the p.N317S mutant receptor after the AVP and DDAVP administration, as assessed by cAMP production was reduced and impaired when compared to cells that expressed the wild type AVPR2 gene. In conclusion, the affected members of this family have X-linked NDI with partial resistance to AVP, due to a missense mutation in the AVPR2 gene.     

Nephrogenic diabetes insipidus

Nephrogenic diabetes insipidus (NDI) is a rare disease characterized by polyuro-polydipsic syndrome (> 30 ml/kg/day in adult) related to an inability to concentrate the urine secondary to resistance to the antidiuretic action of vasopressin (AVP) or to its V2 agonist, dDAVP. NDI may be congenital or acquired. Congenital NDI, familial in most cases, are related in 90% of cases to mutations of the gene coding for V2 receptor of AVP (X-linked recessive disease), and in 10% of cases, to mutations of the gene encoding for aquaporin 2 (autosomic recessive disease). This water channel is expressed at the apical membrane of principal cells of collecting ducts and mediates water transport across the apical plasma membrane of these cells. It is regulated by AVP in two ways. First, AVP has a short term effect in triggering translocation of aquaporin-2-containing intracytoplasmic vesicles to the apical membrane. Second, AVP has a long term effect in increasing the expression of aquaporin-2 in collecting duct. Acquired NDI are iatrogenic (lithium), or related to electrolytic (hypokalemia) or renal abnormalities. The mechanism of these acquired NDI is a decrease of aquaporin 2 abundance in the renal collecting duct.     

In vitro coexpression and pharmacological rescue of mutant gonadotropin-releasing hormone receptors causing hypogonadotropic hypogonadism in humans expressing compound heterozygous alleles

We analyzed the function of mutant GnRH receptor (GnRHR) pairs associated with compound heterozygous patients showing complete or partial forms of hypogonadotropic hypogonadism. We did this to examine potential interactions between misfolded mutants that may influence net receptor function and response to pharmacological rescue. Nine pairs of GnRHR mutants and an unreported combination (L314X((stop))/R262Q) were studied. Coexpression of each pair of mutants in COS-7 cells resulted in an active predominant effect (Q106R/L266R, A171T/Q106R, T32I/C200Y, and R262Q/A129D mutant GnRHR pairs), an additive effect (R262Q/Q106R, N10K/Q106R, and R262Q/Y284C human GnRHR pairs), or a dominant-negative effect (L314X((stop))/Q106R, Q106R+S217R/R262Q, and L314X((stop))/R262Q GnRHRs). For all combinations, addition of the pharmacoperone IN3 increased both agonist binding and effector coupling. The IN3 response was unpredictable because responses could be either similar, higher, or lower, compared with that exhibited by the less affected mutant. The clinical phenotype in patients expressing complex heterozygous alleles appears to be dictated by both the contribution from each mutant and a dominant-negative effect similar to that reported for mutants and wild-type receptor. Depending on the genotype, partial or full restoration of receptor function in response to pharmacological chaperones may be achievable goals in patients bearing inactivating mutations in the GnRHR gene.     

Correlation between clinical phenotypes and X-inactivation patterns in six female carriers with heterozygote vasopressin type 2 receptor gene mutations

About 90% of patients with congenital nephrogenic diabetes insipidus (NDI) have vasopressin type 2 receptor (V2R) gene mutations that are inherited in an X-linked recessive manner. Although most female carriers are asymptomatic, some female carriers show polydipsia and polyuria. The reason why female carriers show NDI symptoms is explained by skewed X-inactivation. We studied X-inactivation patterns of six female carriers with heterozygote V2R gene mutations. The X-inactivation pattern in peripheral blood leukocytes was examined using methylation analysis of the polymorphic CAG repeat in the androgen receptor gene. Two asymptomatic female carriers showed random X-inactivation (61.9% and 60.7%). Skewed X-inactivation patterns (71.6%, 79.4%, and 91.2%) occurring preferentially to normal X alleles were recognized in three female carriers who showed clinical NDI symptoms. However, in one female carrier who showed clinical NDI symptoms, random X-inactivation (55.4%) was recognized. In conclusion, the clinical NDI phenotypes may correlate with the X-inactivation patterns in female carriers with heterozygote V2R gene mutations. However, in some female carriers, we cannot predict the clinical phenotypes by the evaluation of the X-inactivation patterns in peripheral blood leukocytes, because X-inactivation ratios within an individual are sometimes different between tissues.     

Identification, characterization and rescue of a novel vasopressin-2 receptor mutation causing nephrogenic diabetes insipidus

Objective  X-linked nephrogenic diabetes insipidus (XNDI), caused by mutations in the V2 vasopressin receptor (V2R), is clinically distinguished from central diabetes insipidus (CDI) by elevated serum vasopressin (AVP) levels and unresponsiveness to 1-desamino-8- d -arginine vasopressin (DDAVP). We report two infants with XNDI, and present the characterization and functional rescue of a novel V2R mutation.
Patients  Two male infants presented with poor growth and hypernatraemia. Both patients had measurable pretreatment serum AVP and polyuria that did not respond to DDAVP, suggesting NDI. However, both also had absent posterior pituitary bright spot on MRI, which is a finding more typical of CDI.
Methods  The AVPR2 gene encoding V2R was sequenced. The identified novel missense mutation was re-created by site-directed mutagenesis and expressed in HEK293 cells. V2R activity was assessed by the ability of transfected cells to produce cAMP in response to stimulation with DDAVP. Membrane localization of V2R was assessed by fluorescence microscopy.
Results  Patient 1 had a deletion of AVPR2 ; patient 2 had the novel mutation L57R. In transiently transfected HEK293 cells, DDAVP induced detectable but severely impaired L57R V2R activity compared to cells expressing wild-type V2R. Fluorescence microscopy showed that myc-tagged wild-type V2R localized to the cell membrane while L57R V2R remained intracellular. A nonpeptide V2R chaperone, SR121463, partially rescued L57R V2R function by allowing it to reach the cell membrane.
Conclusions  L57R V2R has impaired in vitro activity that can be partially improved by treatment with a V2R chaperone. The posterior pituitary hyperintensity may be absent in infants with XNDI.     

A novel deletion mutation in the arginine vasopressin receptor 2 gene and skewed X chromosome inactivation in a female patient with congenital nephrogenic diabetes insipidus

X-linked nephrogenic diabetes insipidus (NDI) is a rare inherited disorder caused by mutations in the arginine vasopressin receptor 2 (V2R) gene. The clinical phenotype is fully expressed in hemizygous male patients and is usually asymptomatic in heterozygous females. In the present study, a 51-yr-old Japanese female with congenital NDI and her family members were examined. The patient developed severe hypernatremia accompanied by hypoosmotic polyuria after gynecological surgery, and was unable to concentrate urinary osmolality in response to exogenous vasopressin. Direct sequencing analysis of the propositus and her two affected sons revealed a two-nucleotide deletion change at codon 30 (g.452-453delAC) in the V2R gene, resulting in a frameshift and premature termination in translation at codon 190. The X chromosome inactivation pattern was investigated in the propositus using methylation analysis of the polymorphic CAG repeat in the androgen receptor gene, and the value for relative X chromosome inactivation of one allele was 70.2%. In conclusion, we identified a novel V2R gene mutation in a female patient and her sons with congenital NDI, and her phenotype may be caused by skewed X chromosome inactivation.     

Functional characterization of the molecular defects causing nephrogenic diabetes insipidus in eight families

X-Linked nephrogenic diabetes insipidus (NDI) is a rare inherited disorder characterized by the excretion of abnormal large volumes of diluted urine mainly caused by mutations in the V2 vasopressin receptor (AVPR2) gene. By screening NDI patients for mutations within the AVPR2 gene we have identified three novel (I46K, F105V, I130F) and four recurrent (D85N, R106C, R113W, Q225X) mutations. In addition, a recurrent missense mutation (A147T) within the aquaporin-2 gene was identified in a female patient with autosomal recessive NDI associated with sensorineural deafness. Selected clinical data of the NDI patients were compared with the results from the in vitro studies. Functional analysis of I46K and I130F revealed reduced maximum agonist-induced cAMP responses as a result of an improper cell surface targeting. In contrast, the F105V mutation is delivered to the cell surface and displayed an unchanged maximum cAMP response, but impaired ligand binding abilities of F105V were reflected in a shifted concentration-response curve toward higher vasopressin concentrations. As the extracellularly located F105 is highly conserved among the vasopressin/oxytocin receptor family, functional analysis of this residue implicates an important role in high affinity agonist binding.