Quantification of the Effects of Ionic Strength,Viscosity, and Hydrophobicity on Protein–Ligand Binding Affinity

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Naltrexone and β-funaltrexamine antagonism of the antinociceptive and response rate-decreasing effects of morphine, dezocine, and d-propoxyphene

  Rationale: Patterns of competitive and insurmountable antagonism provide important data to guide the classification and characterization of different types of opioid agonists as well as infer the mechanism of action for agonists. Objective: Experiments with the competitive antagonist, naltrexone, and the insurmountable antagonist, β-funaltrexamine (β-FNA), were conducted to determine whether the antinociceptive and rate-decreasing effects of the opioid agonists dezocine and d-propoxyphene are 1) mediated through μ opioid receptors in rats, and 2) differ from morphine with respect to relative efficacy. Methods: The rat tail-withdrawal assay was used to measure antinociception and a fixed ratio 20 (FR20) schedule of food delivery was used to measure rate suppression. Results: Naltrexone (0.01–1.0 mg/kg) was approximately equipotent as an antagonist of the antinociceptive and rate-decreasing effects of both morphine and dezocine and as an antagonist of the antinociceptive effects of d-propoxyphene. Naltrexone failed to block the rate-decreasing effects of d-propoxyphene. β-FNA (5 and 10 mg/kg) also antagonized the antinociceptive and rate-decreasing effects of morphine and dezocine as well as the antinociceptive effects of d-propoxyphene. β-FNA failed to produce a dose-dependent antagonism of the rate-decreasing effects of d-propoxyphene. Conclusions: These data suggest that the antinociceptive effects of morphine, dezocine, and d-propoxyphene and the rate-decreasing effects of morphine and dezocine are mediated through μ opioid receptors. Overall, high doses of β-FNA produced a greater degree of antagonism of the behavioral effects of dezocine than morphine or d-propoxyphene, confirming other reports that dezocine is a lower efficacy agonist than morphine. Additionally, the degree of antagonism produced by β-FNA was greater for the antinociceptive effects of all three compounds than for the rate-decreasing effects. Received: 14 August 1998 / Final version: 4 December 1998     

Effects of saffron and its constituents, crocin-1, crocin-2, and crocetin on α-synuclein fibrils

Journal of Natural Medicines - Saffron, the stigma of Crocus sativus Linné (Iridaceae family), has been known to inhibit aggregation of β-amyloid, a nerve tissue protein. α-Synuclein...     

Design,Synthesis, and Pharmacological Evaluation of Fluorescent and Biotinylated Antagonists of ρ1 GABAC Receptors

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Combinatorial investigation of the effects of the incorporation of Ti, Si, and Al on the performance of α-Fe2O3 photoanodes

The effect of adding small amounts of Ti, Si, and Al on the photoelectrochemical activity of α-Fe(2)O(3) is investigated using a high-throughput combinatorial method. Quantitative ink jet printing is used to pattern iron oxide and dopant precursors onto conductive glass substrates. Subsequent pyrolysis yields a library of doped iron oxide electrodes that are screened for photoelectrolysis activity by immersing in an electrolyte and scanning a laser over the electrodes to map the photocurrent response. When Si and Al are individually added to iron oxide at the levels we studied, the photoelectrolysis activity decreased whereas low levels of Ti addition enhanced the photocurrents. Synergistic effects were observed resulting in enhanced photocurrents when multiple impurities were added to α-Fe(2)O(3).     

Comparison of the subjective effects of Δ<Superscript>9</Superscript>-tetrahydrocannabinol and marijuana in humans

RATIONALE: There has been controversy about whether the subjective, behavioral or therapeutic effects of whole plant marijuana differ from the effects of its primary active ingredient, Delta(9)-tetrahydrocannabinol (THC). However, few studies have directly compared the effects of marijuana and THC using matched doses administered either by the smoked or the oral form.OBJECTIVE: Two studies were conducted to compare the subjective effects of pure THC to whole-plant marijuana containing an equivalent amount of THC in normal healthy volunteers. In one study the drugs were administered orally and in the other they were administered by smoking.METHODS: In each study, marijuana users (oral study: n=12, smoking study: n=13) participated in a double-blind, crossover design with five experimental conditions: a low and a high dose of THC-only, a low and a high dose of whole-plant marijuana, and placebo. In the oral study, the drugs were administered in brownies, in the smoking study the drugs were smoked. Dependent measures included the Addiction Research Center Inventory, the Profile of Mood States, visual analog items, vital signs, and plasma levels of THC and 11-nor-9-carboxy-THC.RESULTS: In both studies, the active drug conditions resulted in dose-dependent increases in plasma THC levels, and the levels of THC were similar in THC-only and marijuana conditions (except that at the higher oral dose THC-only produced slightly higher levels than marijuana). In both the oral study and the smoking study, THC-only and whole plant marijuana produced similar subjective effects, with only minor differences.CONCLUSION: These results support the idea that the psychoactive effects of marijuana in healthy volunteers are due primarily to THC.     

Does the widespread use of proton pump inhibitors mask,complicate and/or delay the diagnosis of Zollinger–Ellison syndrome?

BACKGROUND: Proton pump inhibitors are potent acid suppressants which, at normal doses, can result in hypergastrinaemia in patients with idiopathic oesophageal reflux disease and in the control of symptoms in most patients with gastrinomas. Therefore, their use could delay or mask the diagnosis of gastrinoma. AIM: To investigate whether the widespread use of proton pump inhibitors masks or complicates the diagnosis of gastrinoma. SUBJECTS AND METHODS: Data from two centres with different referral criteria for suspected gastrinomas were analysed (Gastroenterology Unit, Rome, Italy and National Institutes of Health, Bethesda, MD, USA). The number of referrals and the number of new patients with gastrinoma diagnosed in the years prior to the widespread use of proton pump inhibitors (1986-1992) were compared with the numbers since proton pump inhibitors became widely available (1993-1998). RESULTS: The decrease in referral rate (P=0.0009) and the decrease in the annual rate of gastrinoma diagnosis (P=0.0020) at both centres correlated with the increased use of proton pump inhibitors. At the Italian centre, there was a 62% decrease in annual referrals (P < 0.0001) in the post-proton pump inhibitor period, relative to the pre-proton pump inhibitor period, whereas there was an increase in the rate of referral of other gastrointestinal endocrine tumours. The number of new cases of gastrinoma diagnosed decreased by 40%. At the US centre, the referral rate decreased by 28% (P=0.024) in the post-proton pump inhibitor period. There was also a 43% decrease in the number of new cases diagnosed annually in the post-proton pump inhibitor period (P=0.0012). There was a 2.6-fold increase in the post-proton pump inhibitor period in the percentage of referrals with a false diagnosis of gastrinoma as the cause of hypergastrinaemia (P=0.0040). CONCLUSIONS: In both referral centres, less patients have been referred with a possible diagnosis of gastrinoma and fewer new patients with gastrinoma have been diagnosed since proton pump inhibitors became widely available. These data support the conclusion that, since proton pump inhibitors have been released, the diagnosis of gastrinoma has been masked and will probably be delayed, with the result that patients with gastrinoma will be diagnosed at more advanced stages in their disease course.     

A convenient preparation of a disaccharide motif and its role in the cytotoxicity of the triterpenoid saponin, <Emphasis Type="Italic">α</Emphasis>-hederin

The sugar structures of triterpenoid saponins, such as alpha-hederin, are intimately associated with their antitumor activities and other biological activities. The alpha-L: -rhamnopyranosyl-(1-->2)-alpha-L: -arabinopyranoside group of alpha-hederin alters the cytotoxicity of its aglycon, hederagenin. This study explored the role of this saccharide unit in the cytotoxic effect of alpha-hederin and the possibility of its use as a carrier moiety in prodrugs of anticancer agents. A new convenient and practical procedure for the preparation of 4-methoxybenzoyl-2,3,4-tri-O-benzoyl-alpha-L: -rhamnopyranosyl-(1-->2)-3,4-O-dibenzoyl-beta-L: -arabinopyranoside (2) from 4-methoxybenzoyl-beta-L: -arabinopyranoside was accomplished using four steps with an overall yield of 63%. The use of BF(3)-OEt(2) as a catalyst in the glycosylation step in this procedure had a large advantage over the TMSOTf catalyst used in the usual method. Moreover, the key intermediate obtained in this procedure, 4-methoxybenzoyl-2,3,4-tri-O-benzoyl-alpha-L: -rhamnopyranosyl-(1-->2)-alpha-L: -arabinopyranoside (7), was selectively transformed to 4-methoxybenzoyl-2,3,4-tri-O-benzoyl-alpha-L: -rhamnopyranosyl-(1-->2)-4-O-acetyl-alpha-L: -arabinopyranoside (9) and 4-methoxybenzoyl-2,3,4-tri-O-benzoyl-alpha-L: -rhamnopyranosyl-(1-->2)-3-O-benzoyl-beta-L: -arabinopyranoside (10). These derivatives did not show any cytotoxicity against human cancer cell lines. Thus the 3-O-alpha-L: -rhamnopyranosyl-(1-->2)-alpha-L: -arabinopyranoside could be used as a nontoxic carrier moiety to enhance the activity of anticancer drugs.     

Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2–p53 Interaction

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Does the Environment or the Source of the Population Define Stress Status and Energy Supply in the Freshwater Amphipod, <Emphasis Type="Italic">Gammarus fossarum</Emphasis>?

To investigate the effects of acclimation and/or adaptation on the stress protein (hsc/hsp70) response, adenylate energy charge (ACE), ATP/ADP ratio and both lipid and glycogen supply, specimens of four different populations of the freshwater amphipod Gammarus fossarum (Koch, 1835) were transplanted and exposed at sites with various levels of pollution. Induction of the stress protein response was highest in those gammarids transplanted from nearly unpolluted or just moderately polluted sites to severely polluted stream portions. The lowest hsc/hsp70 levels were found in animals transplanted from the polluted sites to the less polluted sites. In all cases the adenylic energy charge (AEC) and ATP/ADP ratio did not show any deficiency in the cellular energy supply. The amount of energy storage substrates, lipid droplets and glycogen in the hepatopancreas, the main metabolic tissue, was similar in all resident populations. In all these amphipod populations, tolerant phenotypes which had diverged genetically were not revealed; rather, the stress and recovery effects derived from the physiologically regulated, cellular stress response.     

Pharmacological Research of Tetrandrine and Fangchinoline, the Major Components of Stephania Tetrandrae

Purpose: The root of the Chinese herbal remedy Han Fang Ji ( Radix of Stephania Tetrandrae) has been used since antiquity by Chinese physicians as an ahtihypertenion, antirheumatic, analgesic and antipyretic agent. Tetrandrine (TET) and fangchinoline (FAN), the bisbenzylisoquinolide alkaloids, are the major components of Han Fang Ji. TET has been well known as a natural occurred non - specific calcium channel blocker. However, the effects of TET on the cardiovascular system are not fully understood, and that a few of researches about FAN, an another major constituent of Han Fang Ji, are reported. Thus, we have done these studies to investigate and compare the effects of TET and FAN on cardiovascular system,CNS and multi - drug resistance to anticancer drugs for several years.     

A systematic review of the effects of oleoylethanolamide,a high-affinity endogenous ligand of PPAR-α, on the management and prevention of obesity

Along with an increase in overweight and obesity among all age groups, the development of efficacious and safe anti-obesity strategies for patients, as well as health systems, is critical. Oleoylethanolamide (OEA), a high-affinity endogenous ligand of nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-α), plays important physiological and metabolic actions. OEA is derived from oleic acid, a monounsaturated fatty acid, which has beneficial effects on body composition and regional fat distribution. The role of OEA in the modulation of food consumption and weight management makes it an attractive molecule requiring further exploration in obesogenic environments. This systematic review was conducted to assess the effects of OEA on the obesity management, with emphasizing on its physiological roles and possible mechanisms of action in energy homeostasis. We searched PubMed/Medline, Google Scholar, ScienceDirect, Scopus, ProQuest, and EMBASE up until September 2019. Out of 712 records screened, 30 articles met the study criteria. The evidence reviewed here indicates that OEA, an endocannabinoid-like compound, leads to satiation or meal termination through PPAR-α activation and fatty acid translocase (FAT)/CD36. Additionally, the lipid-amide OEA stimulates fatty acid uptake, lipolysis, and beta-oxidation, and also promotes food intake control. OEA also exerts satiety-inducing effects by activating the hedonic dopamine pathways and increasing homeostatic oxytocin and brain histamine. In conclusion, OEA may be a key component of the physiological system involved in the regulation of dietary fat consumption and energy homeostasis; therefore, it is suggested as a possible therapeutic agent for the management of obesity.     

Patient‐perceived problems, compliance, and the outcome of hypertension treatment

Objective: To study the associations between the outcome of antihypertensive therapy with both patient-perceived problems and patient initiated modification of dosage instructions. Design and methods: In this cross-sectional survey, all chronic hypertensives aged less than 75 years (n = 971) visiting nine Finnish pharmacies between May and September of 1996 were asked to participate. Of the 866 agreeing to participate, 482 returned the questionnaire (56%). After excluding persons with missing data, the final study population consisted of 428 hypertensive patients. Information on problems with treatment, the modification of dosage instructions, and blood pressure levels was based on patient self-reports.Results: Two-thirds (68%) of the study population reported suffering from one or more problems. The most common problems were symptoms of high blood pressure and adverse drug effects. Thirty-one percent of the male respondents and 21% of the female respondents reported having modified their dosage instructions. Only 36% of the patients had reached the goal blood pressure (<160/90 mmHg). Patients having problems with hypertension treatment were significantly more likely to have modified their dosage instructions than those without problems (3+ problems, adjusted OR=4.8). Not reaching goal blood pressure levels was sigfinicantly associated with both high number of patient-perceived problems (3+ problems, adjusted OR=2.1) and modification of dosage instructions (adjusted OR=1.9).Conclusion: The poor outcome in antihypertensive therapy is associated with both patient-perceived problems and patient initiated modification of dosage instructions.     

A comparison of the content-, construct- and predictive validity of the cigarette dependence scale and the Fagerström test for nicotine dependence

BACKGROUND: Research showed that the widely used Fagerstrom test for nicotine dependence (FTND) does not cover important aspects of dependence. A new test, the cigarette dependence scale (CDS-12), covers the main elements in DSM-IV and ICD-10 definitions of dependence. We compared the psychometrics of CDS-12, FTND, and CDS-5 and the heaviness of smoking index (HSI), which are short versions of CDS-12 and FTND, respectively. METHODS: Internet survey in 2002-2003. Participants were invited one month after answering the first survey to answer a second survey on smoking status and withdrawal symptoms. RESULTS: Eight hundred two smokers answered both surveys. Cronbach's alpha coefficients were higher for CDS-12 (0.91) and CDS-5 (0.77) than for FTND (0.68) and HSI (0.63). Among 231 smokers who quit smoking at follow-up, higher baseline CDS-12 scores predicted higher withdrawal ratings at follow-up, for all withdrawal symptoms except appetite. FTND and HSI predicted higher craving in quitters, but did not predict the intensity of other withdrawal symptoms. Neither CDS-5, FTND or HSI predicted smoking cessation, but higher CDS-12 scores marginally predicted smoking cessation at follow-up (area under the receiver operating characteristic (ROC) curve = 0.55, 95% confidence interval = 0.51-0.59). CONCLUSIONS: CDS-12 had better content validity and internal consistency than FTND and was a slightly better predictor of withdrawal symptoms. Unexpectedly, higher (not lower) CDS-12 scores predicted subsequent smoking cessation, perhaps because endorsement of some CDS-12 items implies accepting that one is dependent, which in turn could reflect motivation to quit. CDS-12 may represent an alternative to FTND for measuring cigarette dependence.     

Contamination and Biomarkers in the Great Blue Heron, an Indicator of the State of the St. Lawrence River

In 1996–1997, nine breeding colonies of the great blue heron on the St. Lawrence River and its estuary (Québec, Canada) were investigated in the framework of a biomonitoring program. Fledglings from colonies in freshwater were more contaminated with mercury, PCBs and many organic contaminants than those from estuarine colonies. The level of contamination in the St. Lawrence River is generally below the levels of toxicological effects for the great blue heron. The molar ratio of retinol: retinyl palmitate in heron eggs was correlated with total PCBs (r=0.79) and Mirex (r=0.90). In plasma, all biochemical parameters were significantly different between freshwater and marine colonies. Plasma retinol concentrations at the Dickerson and Hérons colonies were significantly lower compared with those at Grande Ile (p<0.05) and Steamboat (p<0.001). Based on retinoid and β-carotene concentrations in eggs, low plasma retinol was not associated with possible dietary deficiency. Plasma retinol was negatively correlated with many PCB congeners, total PCBs (r=−0.78), p,p′-DDE, trans-nonachlor and α-HCH. Similarly, the hormone T3 was correlated with many PCB congeners, total PCBs (r=−0.69) and the same organochlorine chemicals. Plasma LDH concentrations were different among freshwater colonies, Grande Ile and Hérons colonies having LDH values significantly greater than those of Steamboat (respectively, p<0.05 and p<0.01). Globally, the health status of the St. Lawrence great blue heron population was judged to be acceptable, however, several biomarkers indicated positive responses to contaminants.     

Effect of low doses of Δ<Superscript>9</Superscript>-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats

Rationale Using the place-preference conditioning paradigm, we evaluated the potential of the two most prominent cannabinoids found in marijuana, the psychoactive component ⁹-tetrahydrocannabinol (⁹-THC) and the nonpsychoactive component cannabidiol (CBD), to potentiate extinction of a cocaine-induced and an amphetamine-induced conditioned place preference in rats.Methods To determine the effects of pretreatment with ⁹-THC or CBD on extinction, a cocaine-induced and amphetamine-induced place preference was first established. Rats were then given an extinction trial, during which they were confined to the treatment-paired floor for 15 min. Thirty minutes prior to the extinction trial, they were injected with a low dose of ⁹-THC (0.5 mg/kg), CBD (5 mg/kg) or vehicle. The potential of the CB₁ receptor antagonist, SR141716, to reverse the effects of ⁹-THC or CBD was also evaluated. To determine the hedonic effects of CBD, one distinctive floor was paired with CBD (5 mg/kg) and another with saline. Finally, to determine the effect of ⁹-THC or CBD on the establishment and/or the expression of a place preference during four cycles of conditioning trials, rats were injected with ⁹-THC (0.25–1 mg/kg), CBD (5 mg/kg) or vehicle 25 min prior to receiving an injection of amphetamine followed by placement on the treatment floor; on alternate days, they received injections of vehicle followed by saline and placement on the nontreatment floor. The rats then received two test trials; on one trial they were pretreated with the cannabinoid and on the other trial with vehicle.Results ⁹-THC and CBD potentiated the extinction of both cocaine-induced and amphetamine-induced conditioned place preference learning, and this effect was not reversed by SR141716. The cannabinoids did not affect learning or retrieval, and CBD was not hedonic on its own.Conclusions These results are the first to show that both ⁹-THC, which acts on both CB1 and CB2 receptors, and CBD, which does not bind to CB₁ or CB₂ receptors, potentiate the extinction of conditioned incentive learning.     

Ionic liquid – microemulsions assisting in the transdermal delivery of Dencichine: Preparation,in-vitro and in-vivo evaluations,and investigation of the permeation mechanism

A novel microemulsion was developed and characterized for topical delivery of Dencichine (Den). Two imidazaolium ionic liquid, 1-hydroxyethyl-3-methylimidazolium chloride ([HOEIM]Cl) and 1-butyl-3-methylimidazolium dodecanesulfate ([BMIM]C₁₂SO₃) were incorporated into the aqueous and surfactant phases respectively for the remarkable enhancement on skin permeation. The nano-carrier was developed and optimized based on a pseudo-ternary phase diagram. The optimized formulation was composed of 50% water/[HOEIM]Cl mix (1:1) as water phase, 20% Tween 80/[BMIM]C₁₂SO₃ mix (1:1) as surfactant, 10% propylene glycol as co-surfactant and 20% IPM as oil phase. The o/w microemulsion was then characterized for droplets sizes (47.7 ± 1.5 nm), zeta potential (?14.83 ± 3.64 mV), viscosity (31 ± 4 mPa) and pH (6.71 ± 0.04). In-vitro skin permeation assay suggested the strong enhancement of ILs formulation on the topical delivery of Den, which was approximately 10-fold that of the drug aqueous solution. It was found that the nano-carrier can reduce the skin barrier properties by disrupting the regular and compact arrangements of corneocytes, and moderating the surface properties of the stratum corneum, as evidenced by Transdermal Water Loss Evaluation (TEWL), Differential Scanning Calorimetery (DSC) and attenuated total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR). Furthermore, the in-vivo pharmacodynamic evaluation indicated the significant hemostatic activity of Den by the topical application of the vehicle. Additionally, the formulation showed minor cell toxicity and skin irritation. Therefore, our work suggested that the ionic liquid microemulsion can be a promising nano-scale vehicle for the topical application of Den to produce desirable pharmacological effects.