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1.
《Expert opinion on therapeutic targets》2013,17(1):73-77
Anorexia and body weight loss are characteristic of many diseases, including cancer and AIDS. Neuropeptides play a pivotal role in the physiological mechanisms regulating food intake and body weight. Neuropeptide Y (NPY) is a key molecule of the orexigenic network for energy intake and for normal adaptive feeding response to energy deficits. Therefore, the NPY receptors (notably, Y1 and Y5) may be one of the most significant target classes for treatment of anorexia and body weight loss. In addition, several anorexigenic peptides including corticotropin-releasing factor (CRF), cholecystokinin (CCK), leptin and melanocortin (MC) are emerging as potential targets for anorexia. Antagonists for CRF 2 receptor, CCK A receptor, MC 4 receptor and leptin receptor may be useful in stimulating food intake. The development of highly specific and selective non-peptide antagonists for these receptors is awaited. Anorexia is a crucial and critical disease. Increasing knowledge of its pathophysiology could lead to innovative new medicines for anorexia-cachexia syndrome. 相似文献
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Monica Mazzarino Fabio Comunità Xavier de la Torre Francesco Molaioni Francesco Botrè 《Drug testing and analysis》2021,13(10):1712-1726
This article reports the results obtained from the investigation of the influence of miconazole administration on the physiological fluctuation of the markers of the steroid profile included in the “steroidal module” of the Athlete Biological Passport. Urines collected from male Caucasian subjects before, during, and after either systemic (i.e., oral and buccal) or topical (i.e., dermal) treatment with miconazole were analyzed according to validated procedures based on gas chromatography coupled to tandem mass spectrometry (GC–MS/MS) (to determine the markers of the steroid profile) or liquid chromatography coupled to MS/MS (LC–MS/MS) (to determine miconazole urinary levels). The results indicate that only after systemic administration, the markers of the steroid profile were significantly altered. After oral and buccal administration, we have registered (i) a significant increase of the 5α-androstane-3α,17β-diol/5β-androstane-3α,17β-diol ratio and (ii) a significant decrease of the concentration of androsterone, etiocholanolone, 5β-androstane-3α,17β-diol, and 5α-androstane-3α,17β-diol and of the androsterone/etiocholanolone, androsterone/testosterone, and 5α-androstane-3α,17β-diol/epitestosterone ratios. Limited effects were instead measured after dermal intake. Indeed, the levels of miconazole after systemic administration were in the range of 0.1–12.5 μg/ml, whereas after dermal administration were below the limit of quantification (50 ng/ml). Significant alteration started to be registered at concentrations of miconazole higher than 0.5 μg/ml. These findings were primarily explained by the ability of miconazole in altering the kinetic/efficacy of deglucuronidation of the endogenous steroids by the enzyme β-glucuronidase during the sample preparation process. The increase of both incubation time and amount of β-glucuronidase was demonstrated to be effective countermeasures in the presence of miconazole to reduce the risk of uncorrected interpretation of the results. 相似文献
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Li Shu - hui Li Xiao - hui Hu De - yao Wang Zheng - guo 《中国药理通讯》2005,22(4):51-52
In the present study, we attempt to analyse the potential involvement of the opioid receptor gene expression in the mechanisms of the analgesic action of melatonin. A trauma-pain model was established in Wistar rats by combining right - hind limb amputation with 50℃ tail - flick test. Antinociception was determined by tail-flick latency to hot waster at 50℃. Melatonin produced the antinociceptive effect in dose-dependent manner after i. p or i. c.v. administration Injected i. c. v. to rats, naloxone(10μg) obviously antagonized the antinociceptive effect induced by i.p. melatonin. 相似文献
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Despite the dramatic success of pharmacological acid suppression in healing peptic ulcers (PUs) and managing patients with gastro-esophageal reflux disease (GERD) a number of challenges remain in the management of acid-related disorders. Several new drugs are currently being investigated to provide a significant advance over current treatments. These include new drug formulations, novel proton pump inhibitors (PPIs) as well as potassium-competitive acid blockers (P-CABs), which have already reached clinical testing. Some others (like NO-releasing antisecretory compounds) are still in preclinical development and require proof of concept in humans. While H(2)-receptor antagonists (especially soluble or OTC formulations) will become the 'antacids of the third millennium' and will be particularly useful for on-demand symptom relief, clinicians will continue to rely on PPIs to control acid secretion in GERD and other acid-related diseases. Since an increasing proportion of patients fail to respond to the best PPI treatment, more potent and long-acting drugs and more effective regimens are needed. 相似文献
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Gases such as nitric oxide and carbon monoxide play important roles both in normal physiology and in disease. In recent years, interest has been directed towards other naturally occurring gases, notably hydrogen sulfide (H2S), which is both a potent vasodilator and a mediator of long-term potentiation in the brain. This article focuses on recent work that suggests a role for H2S, and perhaps other gases, in the CNS and cardiovascular system. 相似文献
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Hajime Kawasaki 《Inhalation toxicology》2019,31(1):25-34
The distribution of dust particles within the lungs and their excretion are highly associated with their pulmonary toxicity. Literature was reviewed to discern pulmonary translocation pathways for inhaled α-quartz compared to those for inhaled TiO2. Accordingly, it was hypothesized α-quartz particles in the alveoli were phagocytized by alveolar macrophages but silica-containing macrophages remained in the alveoli for longer time in contrast to the rapid elimination from the alveoli seen for TiO2-containing macrophages. In addition, it was presumed that free silica particles are translocated in the interstitium, possibly through the cytoplasm of Type I epithelial cells, as observed with TiO2. Free silica particles are presumed to be phagocytized by interstitial macrophages soon after the particles penetrate the interstitium; these dust cells are then translocated to the ciliated airway regions in the lumen through bronchus-associated lymphoid tissue (BALT). The pulmonary retention half-time of dust particles in rats exposed to α-quartz is several times longer than that of rats exposed to TiO2, as long as the lung dust burden is ≈ 3?mg. The reduced pulmonary particle clearance ability in rats exposed to α-quartz aerosol is presumably attributed to the long-term retention of dust cells both in the alveoli and in the interstitium; this retention may be caused by the reduced chemotactic abilities of α-quartz-containing dust cells. However, the accumulation of α-quartz-containing dust cells in the lungs is not associated with the occurrence of pulmonary inflammation. 相似文献
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Summary When slices of rat dorsal caudatoputamen (= neostriatum) are incubated in vitro, Choecystokinin-like immunoreactivity (CCK-LI) is released upon addition of veratridine (3.75 mol/l). This release is affected by dopamine and by -aminobutyric acid (GABA)-receptor agonists. Dopamine enhances the release by stimulating dopamine D2-receptors and decreases it via D1-receptors. GABAA-receptor agonists enhance the veratridine-induced release of CCK-LI, while GABAB-receptor agonists decrease it. In the present investigation, it was examined whether GABA-receptors are involved in the effect which dopamine exerts via D2-receptors. The GABAA-receptor antagonist bicuculline (10 mol/l)and the blocker of the GABAA-receptor ionophore picrotoxin (1 mol/l) did not affect the dopamine (0.1 mol/1)-induced increase in the release of CCK-LI. However, the GABAA-receptor agonist muscimol (1 mol/l) not only enhanced the release of CCK-LI, but also prevented a further enhancement by dopamine (0.1 mol/l). This effect of muscimol was blocked by bicuculline (10 mol/l). In the presence of -amino-n-valeric acid (0.1 mmol/l), which has been described to block GABAB-receptors, dopamine no longer enhanced the veratridine-induced release of CCK-LI. -Amino-n-valeric acid also inhibited the pronounced enhancement of the release of CCK-LI caused by dopamine (0.1 mol/l) and 1 mol/l in the presence of the preferential D1-receptor antagonist SCH 23390. The effect of -amino-n-valeric acid persisted in the presence of bicuculline (10 mol/l and 100 mol/l). (+)-Baclofen, a partial agonist at GABAB-receptors, and the stereoisomer (–)-baclofen, a full agonist, also prevented the effect of dopamine on the veratridine-induced release of CCK-LI. The effects of both drugs may be due to desensitization of GABAB-receptors, which has been described to develop quite rapidly. It is concluded that -amino-n-valeric acid blocks GABAB-receptors and in this way prevents the enhancement of the veratridine-induced release of CCK-LI caused by dopamine via D2-receptors. These data are interpreted as evidence that dopamine and GABA-neurons can directly or indirectly interact in the rat neostriatum.
Send offprint requests to D. K. Meyer at the above address 相似文献
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Carl Dahlöf Göran Engberg Torgny H. Svensson 《Naunyn-Schmiedeberg's archives of pharmacology》1981,317(1):26-30
Summary Acute i.v. administration of the non-selective -adrenoceptor antagonist dl-propranolol given in incremental doses (<40 mg/kg) did not affect the firing rate of locus coeruleus (LC) neurones in the rat, as revealed by single cell recording techniques. Furthermore, no effect was seen 4 h after a single i.p. dose of this -blocker (10 mg/kg). However, repeated treatment with dl-propranolol (1, 5, 10 or 20 mg/kg i.p., twice daily for 4 days) produced a significant, dose-dependent decrease of the average LC neuronal firing rate in comparison to controls. The dextro isomer of propranolol, which has negligible -blocking activity but the same local anaesthetic potency as the racemate, had no corresponding effect. The non-selective -adrenoceptor antagonist sotalol, which is one of the most hydrophilic -blockers, had much less inhibitory effect on LC neurones than dl-propranolol. The 1-selective antagonist metoprolol did not change the firing of noradrenergic neurones in the LC after similar treatment for 4 days. However, when the rats were subjected to oral treatment for 28 days, metoprolol was found to produce a slight inhibitory effect although much less than dl-propranolol.In view of these findings we propose a stimulatory and mainly 2-adrenoceptor-mediated control mechanism for the noradrencrgic neurones in the LC. This mechanism seems to be characterized by a delayed responsiveness. 相似文献
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Aim: To study the effect of Ecdysterone (ECR) on the expression of Tau from the cerebral cortice and hippocampus and behaviors in passive avoidance reaction and spatial discrimination of the mice induced by overload aluminum salt.Methods Fourty-five NIH mice were randomly divided into five groups, the control group, the model group, the treated 相似文献
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Ellen Berni Daniel Murphy James Whitehouse Pete Conway Paola Di Maggio 《Current medical research and opinion》2013,29(11):2001-2008
Objective: Rifaximin-α 550?mg twice daily plus lactulose has demonstrated efficacy in reducing recurrence of episodes of overt hepatic encephalopathy (OHE) and the risk of hepatic encephalopathy (HE)-related hospitalizations compared with lactulose alone. This analysis estimated the cost effectiveness of rifaximin-α 550?mg twice daily plus lactulose versus lactulose alone in United Kingdom (UK) cirrhotic patients with OHE.Method: A Markov model was built to estimate the incremental cost-effectiveness ratio (ICER). The perspective was that of the UK National Health Service (NHS). Clinical data was sourced from a randomized controlled trial (RCT) and an open-label maintenance study in cirrhotic patients in remission from recurrent episodes of OHE. Health-related utility was estimated indirectly from disease-specific quality of life RCT data. Resource use data describing the impact of rifaximin-α on hospital admissions and length of stay for cirrhotic patients with OHE was from four single-center UK audits. Costs (2012) were derived from published sources; costs and benefits were discounted at 3.5%. The base-case time horizon was 5 years.Results: The average cost per patient was £22,971 in the rifaximin-α plus lactulose arm and £23,545 in the lactulose arm, a saving of £573. The corresponding values for benefit were 2.35 quality adjusted life years (QALYs) and 1.83 QALYs per person, a difference of 0.52 QALYs. This translated into a dominant base-case ICER. Key parameters that impacted the ICER included number of hospital admissions and length of stay.Conclusion: Rifaximin-α 550?mg twice daily in patients with recurrent episodes of OHE was estimated to generate cost savings and improved clinical outcomes compared to standard care over 5 years. 相似文献
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G. Wiemer A. Wellstein D. Palm H. M. v. Hattingberg D. Brockmeier 《Naunyn-Schmiedeberg's archives of pharmacology》1982,321(1):11-19
Summary To study the fundamental differences between agonist and antagonist interaction with the -adrenoceptor of the rat reticulocyte the radiolabeled agonist3H hydroxybenzylisoprenaline (3H HBI) and the radiolabeled antagonist3H dihydroalprenolol (3H DHA) were used.Equilibrium binding experiments with3H HBI revealed all characteristics expected to a -adrenoceptor site, i. e. high affinity binding (K
D
high=7.4±0.9×10–9 M), saturability (B
max
high=230±24 fmoles/mg protein), and stereoselectivity. The rank order of potency for competing agonists was isoprenaline > adrenaline > noradrenaline > dopamine.3H HBI high affinity binding sites amounted to about 25% of -adrenoceptor sites detectable with3H DHA.In competition experiments with3H HBI and (-)isoprenaline[(-)Ipn]aK
D
high-value for (-)Ipn of 3.1±0.6×10–8M was obtained corresponding to theK
D
high-value of (-)Ipn obtained from competition experiments using3H DHA. For (-)propranololK
D-values of 0.9±0.5×10–8 M and 1.0 ±1.0×10–8 M were measured using3H HBI and3H DHA respectively.Agonist affinity derived from competition experiments with (-)Ipn versus3H DHA was not affected by temperature changes.Guanylyl-imidodiphosphate [Gpp(NH)p] decreased concentration dependently the number of high affinity binding sites of3H HBI not affecting the respectiveK
D-value. Similar effects were observed after omission of Mg2+ from the binding assay or inclusion of Na+ in the Mg2+-free incubation mixture.The association reaction of3H HBI at the -adrenoceptor revealed two different velocities. The slower phase of the association reaction which represents high affinity binding (80% of equilibrium binding) is not observed in the presence of Gpp(NH)p.A biphasic dissociation of3H HBI binding was induced by 10–4 M (±)propranolol: 25% dissociated with at
1/2 of 1.3 min whereas the high affinity binding was reversed with at
1/2 of 150 min. This slowly reversible binding of3H HBI however was rapidly reversed by Gpp(NH)p (t
1/2<1 min).It is concluded that the agonist ligand3H HBI permits a direct qualitative and quantitative characterization of the agonist induced high affinity state of the -adrenoceptor. In particular, the kinetic studies strongly support a two step binding model for the agonist--adrenoceptor interaction.This work was supported by a grant from the Deutsche ForschungsgemeinschaftParts of this work were presented at the Spring Meetings of the German Pharmacological Society (Wiemer et al. 1978, 1981 b)Herrn Professor Dr. med. Hans Herken, Pharmakologisches Institut der Freien Universität Berlin, zum 70. Geburtstag gewidmet. 相似文献
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Laura E. Russell Mary Alexandra Schleiff Eric Gonzalez Aaron G. Bart Fabio Broccatelli Jessica H. Hartman 《Drug metabolism reviews》2020,52(3):395-407
AbstractThe 12th International Society for the Study of Xenobiotics (ISSX) meeting, held in Portland, OR, USA from July 28 to 31, 2019, was attended by diverse members of the pharmaceutical sciences community. The ISSX New Investigators Group provides learning and professional growth opportunities for student and early career members of ISSX. To share meeting content with those who were unable to attend, the ISSX New Investigators herein elected to highlight the “Advances in the Study of Drug Metabolism” symposium, as it engaged attendees with diverse backgrounds. This session covered a wide range of current topics in drug metabolism research including predicting sites and routes of metabolism, metabolite identification, ligand docking, and medicinal and natural products chemistry, and highlighted approaches complemented by computational modeling. In silico tools have been increasingly applied in both academic and industrial settings, alongside traditional and evolving in vitro techniques, to strengthen and streamline pharmaceutical research. Approaches such as quantum mechanics simulations facilitate understanding of reaction energetics toward prediction of routes and sites of drug metabolism. Furthermore, in tandem with crystallographic and orthogonal wet lab techniques for structural validation of drug metabolizing enzymes, in silico models can aid understanding of substrate recognition by particular enzymes, identify metabolic soft spots and predict toxic metabolites for improved molecular design. Of note, integration of chemical synthesis and biosynthesis using natural products remains an important approach for identifying new chemical scaffolds in drug discovery. These subjects, compiled by the symposium organizers, presenters, and the ISSX New Investigators Group, are discussed in this review. 相似文献
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Summary By osmotic lysis in the presence of urea ghosts (60–100 nmol catecholamine/mg prot.) were prepared from chromaffin granules (4–6 mol catecholamine/mg prot.) of the bovine adrenal medulla. In the presence of 1–300 mol/l3H-catecholamine and ATP-Mg2+, ghosts show a net uptake of catecholamine. The net uptake is sensitive to reserpine or agents (uncouplers and ammonium) which diminish the electrochemical potential difference for protons at the granule membrane (p). The same uptake was found by3H-counting or by fluorimetric measurements. At various pH-values (pH 6.2–82.) theK
m andV
max of the ATP-stimulated rate of uptake of3H-catecholamine into ghosts was determined (at 30°C) to identify the species of catecholamine (protonated, uncharged, or anionic) which is the substrate for the granule carrier. The pH difference (pH=pHout-pHin) and the electrical potential difference () were determined to calculate p under conditions of3H-catecholamine uptake. When the pHout was increased (pH 6.2, 7.4, 8.2), the apparentK
m of uptake decreased (50, 5, 1–2 mol/l), showing a linear relation between pH and logarithm ofK
m. TheK
m was calculated for the uncharged catecholamine (with pK1=8.8 and pK2=10.0); it was nearly pH-independent and amounted to about 0.2 mol/l. TheV
max declined only in the extreme pH-range. Between pH 6.6 and 7.8V
max and p showed a slight increase from 16 to 20 nmoles/(mg prot.·min) and from 110 to 140 mV, resp. In the same pH-range the pHin inside ghosts increased from pH 5.2 to 5.7, whereas was constant (30 mV). At constant pHout (=7.3) ammonium (0–30 mmol/l) caused an increase of pHin from 5.5 to 6.6. The increase of pHin was accompanied by an increase ofK
m from 5 to 20 mol/l3H-catecholamine and by a decrease of bothV
max and p from 20 to 5 nmoles/(mg prot.·min) and from 123 to 85mV, respectively. From the dependence of theK
m of uptake on pHout is concluded that the uncharged species of catecholamine is transported, whereas the dependence ofK
m on pHin suggests that the translocation of the catecholamine-carrier complex across the granule membrane is not the rate-limiting step of catecholamine uptake.A preliminary account was presented to the Deutsche Pharmakologische Gesellschaft (Kobold and Burger 1983) 相似文献
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Summary Membrane currents were measured in single sino-atrial node cells of guinea pig and rabbit hearts as well as in guinea pig ventricular myocytes using the patch-clamp technique. UL-FS 49 blocked the L-type calcium current (ICa) in sino-atrial node cells at drug concentrations wich had little or no effect on the amplitude of the hyperpolarization-activated current ih(f). In guinea pig ventricular myocytes UL-FS 49 also blocked ICa but not as strongly as in sino-atrial node cells. In a computer simulation of the sino-atrial node action potential the extent of rate reduction by block of either ih(f) or ICa was estimated. From the data obtained by single cell measurements and the computations we concluded that rate reduction in primary pacemaker cells by application of UL-FS 49 is mainly due to a use dependent block of the L-type calcium current. Voltage dependent unblock of iCa at potentials more negative than –50 mV together with the lower drug sensitivity of ventricular cells can explain the specific bradycardic action of UL-FS 49.
Send offprint requests to W. Trautwein at the above address 相似文献