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41.
The human dopamine D2(Longer) receptor has a high-affinity state and inhibits adenylyl cyclase 总被引:1,自引:0,他引:1
Brain dopamine D2 receptors are the main targets for antipsychotic and anti-Parkinsonian drugs. The dopamine D2 receptor has three forms, D2(Short), D2(Long) and D2(Longer). D2(Longer) is a newly found splice variant which contains two additional amino acids (valine and glutamine) in the third cytoplasmic loop of the receptor. To determine whether D2(Longer) was functional, the cDNA was transfected into CHO cells. D2(Longer) revealed a high-affinity state for dopamine ( approximately 1.5 nM), and mediated dopamine-inhibited adenylyl cyclase. 相似文献
42.
Antipsychotic agents differ in how fast they come off the dopamine D2 receptors. Implications for atypical antipsychotic action 总被引:4,自引:0,他引:4
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RATIONALE AND OBJECTIVE: While the blockade of dopamine D2 receptors are necessary for antipsychotic action, antipsychotic agents differ nearly a thousand-fold in their affinity for the D2 receptor. This affinity is determined by the rate at which the antipsychotic agent binds to (kon) and the rate at which it dissociates from (koff) the D2 receptors. The objective of this study was to determine the relationship between kon, koff and the affinity (Ki) of antipsychotic agents for the D2 receptors, with particular reference to typical and atypical antipsychotic agents. DESIGN: The koff of several typical as well as atypical antipsychotic agents (nemonapride, spiperone, haloperidol, chlorpromazine, raclopride, olanzapine, sertindole, clozapine and quetiapine) was measured in vitro using the 3H-radiolabelled analogues of these drugs. The affinity of these drugs for the D2 receptor was determined by competition with 3H-raclopride in vitro. The kon was derived from values of affinity and ++koff. MAIN OUTCOME MEASURES: kon, koff, and the Ki of antipsychotic drugs. RESULTS: The range of affinity values was similar to that conventionally accepted (0.025-155 nmol/L). The koff values varied a thousand-fold from 0.002 to 3.013 min-1, with relatively little variation in kon. The rate at which antipsychotic agents come off the receptor (koff) accounted for 99% of the variation in their affinity for the D2 receptor; differences in kon did not account for differences in affinity. CONCLUSIONS: The differences in the affinity of antipsychotic agents are entirely determined by how fast they come off the D2 receptor. These differences in koff may lead to functionally different kinds of dopamine blockade. Drugs with a higher koff will be faster in blocking receptors, and once blocked, will provide more access to surges in dopamine transmission. Since atypical drugs show a lower affinity and a faster dissociation, a higher koff for the D2 receptor is proposed as a mechanism for "atypical" antipsychotic effect. 相似文献
43.
I. Borgulová R. Mazanec I. Sakmaryová M. Havlová D. Šafka Brožková P. Seeman 《Neurogenetics》2013,14(3-4):189-195
Charcot-Marie-Tooth (CMT) disease is a heterogeneous disorder of the peripheral nervous system that collectively affects approximately 1 in 2,500 individuals, thus making it the most common inherited neurologic disorder. X-linked inheritance may account for 10–20 % of CMT neuropathy. We report a Czech family with a 30-year-old woman affected by CMT since the age of 10 years, originally as an isolated case. Nerve conduction study (NCS) showed demyelinating neuropathy, and DNA testing revealed a novel heterozygous gap junction beta-1 protein (GJB1) mutation c.784_786delTA. The same mutation, but surprisingly in heterozygous state, was subsequently found in her subjectively healthy father and later also in one of her sisters but not in her two other sisters. NCS showed intermediate type of motor and sensory neuropathy in these two females manifesting heterozygotes and normal results in the other healthy sisters and one brother, all without the c.784_786delTA mutation. The father has a phenotype milder than his daughter and has only subclinical signs of CMT. The index female patient had normal karyotype 46, XX, and normal FISH for centromeric X chromosome. We concluded that the proband’s father is a heterozygote due to the somatic mosaicism for the GJB1 mutation in his leukocytes (detected by DNA sequencing) and also in his germ cells as confirmed by the unexpectedly different genotypes in his four daughters. Quantitative analysis revealed a mutated signal in 25:75 allele proportion of mutated to healthy allele in the mosaic father. This study has important consequences for genetic counseling and prognosis in CMTX1 families. 相似文献
44.
Background
The construction of prediction intervals (PIs) for future body mass index (BMI) values of individual children based on a recent German birth cohort study with n = 2007 children is problematic for standard parametric approaches, as the BMI distribution in childhood is typically skewed depending on age. 相似文献45.
Marcus Maurer Markus Magerl Martin Metz Torsten Zuberbier 《Journal der Deutschen Dermatologischen Gesellschaft》2013,11(10):971-978
At the end of 2012, more than 300 participants discussed and agreed on the update of the international guidelines on urticaria at the 4th International Consensus Meeting (URTICARIA 2012). Currently, the recommendations are in the final process of international coordination. In preparation for the update, questions were prepared by an expert panel; this was followed by a systematic literature search. The questions and the resulting recommendations were discussed by the participants and decided upon in an open vote. Consensus was defined as at least 75% agreement. The updated guidelines will modify and improve the currently available guidelines in various areas, especially in therapy. For the treatment of chronic urticaria, the new algorithm recommends a three‐step process starting with a standard dose of a non‐sedating H1 antihistamine. If there is an insufficient treatment response, the dosage should be increased up to four times. In, therapy refractory patients, omalizumab, cyclosporine A, or montelukast are advised in the third step. Short‐term corticosteroid treatment for a maximum of 10 days may be considered. H2 antihistamines and dapsone, which were included in the previous version of the guidelines, are absent in the updated and revised version because of changes in the evidence level. 相似文献
46.
In this text, we present and elaborate ethical challenges in transplant medicine related to organ procurement and organ distribution, together with measures to solve such challenges. Based on internationally acknowledged ethical standards, we looked at cases of organ procurement and distribution practices that deviated from such ethical standards. One form of organ procurement is known as commercial organ trafficking, while in China the organ procurement is mostly based on executing prisoners, including killing of detained Falun Gong practitioners for their organs. Efforts from within the medical community as well as from governments have contributed to provide solutions to uphold ethical standards in medicine. The medical profession has the responsibility to actively promote ethical guidelines in medicine to prevent a decay of ethical standards and to ensure best medical practices. 相似文献
47.
48.
Torsten Fredriksson M.D. Jerry K. Bigelow M.T. 《Archives of environmental & occupational health》2013,68(6):663-667
Repeated inhalation of the vapors of bis(chloromethyl) ether and chloromethyl methyl ether at one and two ppm, respectively, and of the aerosol of urethan at approximately 138 ppm, resulted in an increase in incidence of pulmonary adenomas in strain A mice. In addition, the high toxicity of the two haloethers and the general lack of properties irritating to the upper respiratory tract in all three compounds pose an insidious industrial handling hazard. 相似文献
49.
Licia Iaccarino Tiziana Ottone Valentina Alfonso Laura Cicconi Mariadomenica Divona Serena Lavorgna Serena Travaglini Aleandra Ferrantini Giulia Falconi Constance Baer Monica Usai Fabio Forghieri Adriano Venditti Maria Ilaria Del Principe William Arcese Maria Teresa Voso Torsten Haferlach Francesco Lo-Coco 《American journal of hematology》2019,94(10):1091-1097
Despite the high probability of cure of patients with acute promyelocytic leukemia (APL), mechanisms of relapse are still largely unclear. Mutational profiling at diagnosis and/or relapse may help to identify APL patients needing frequent molecular monitoring and early treatment intervention. Using an NGS approach including a 31 myeloid gene-panel, we tested BM samples of 44 APLs at the time of diagnosis, and of 31 at relapse. Mutations in PML and RARA genes were studied using a customized-NGS-RNA panel. Patients relapsing after ATRA-chemotherapy rarely had additional mutations (P = .009). In patients relapsing after ATRA/ATO, the PML gene was a preferential mutation target. We then evaluated the predictive value of mutations at APL diagnosis. A median of two mutations was detectable in 9/11 patients who later relapsed, vs one mutation in 21/33 patients who remained in CCR (P = .0032). This corresponded to a significantly lower risk of relapse in patients with one or less mutations (HR 0.046; 95% CI 0.011-0.197; P < .0001). NGS-analysis at the time of APL diagnosis may inform treatment decisions, including alternative treatments for cases with an unfavorable mutation profile. 相似文献
50.
Denise Lego Markus Plaumann Thomas Trantzschel Joachim Bargon Henning Scheich Gerd Buntkowsky Torsten Gutmann Grit Sauer Johannes Bernarding Ute Bommerich 《NMR in biomedicine》2014,27(7):810-816
Parahydrogen‐induced polarization (PHIP) is a promising new tool for medical applications of MR, including MRI. The PHIP technique can be used to transfer high non‐Boltzmann polarization, derived from parahydrogen, to isotopes with a low natural abundance or low gyromagnetic ratio (e.g. 13C), thus improving the signal‐to‐noise ratio by several orders of magnitude. A few molecules acting as metabolic sensors have already been hyperpolarized with PHIP, but the direct hyperpolarization of drugs used to treat neurological disorders has not been accomplished until now. Here, we report on the first successful hyperpolarization of valproate (valproic acid, VPA), an important and commonly used antiepileptic drug. Hyperpolarization was confirmed by detecting the corresponding signal patterns in the 1H NMR spectrum. To identify the optimal experimental conditions for the conversion of an appropriate VPA precursor, structurally related molecules with different side chains were analyzed in different solvents using various catalytic systems. The presented results include hyperpolarized 13C NMR spectra and proton images of related systems, confirming their applicability for MR studies. PHIP‐based polarization enhancement may provide a new MR technique to monitor the spatial distribution of valproate in brain tissue and to analyze metabolic pathways after valproate administration. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献