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1.
Tramadol (T) is available as a racemic mixture of (+)‐trans‐T and (−)‐trans‐T. The main metabolic pathways are O‐demethylation and N‐demethylation, producing trans‐O‐desmethyltramadol ( M1 ) and trans‐N‐desmethyltramadol ( M2 ) enantiomers, respectively. The analgesic effect of T is related to the opioid activity of (+)‐trans‐T and (+)‐ M1 and to the monoaminergic action of (+/−)‐trans‐T. This is the first study using tandem mass spectrometry as a detection system for the simultaneous analysis of trans‐T, M1 , and M2 enantiomers. The analytes were resolved on a Chiralpak® AD column using hexane:ethanol (95.5:4.5, v/v) plus 0.1% diethylamine as the mobile phase. The quantitation limits were 0.5 ng/ml for trans‐T and M1 and 0.1 ng/ml for M2 . The method developed and validated here was applied to a pharmacokinetic study in rats. Male Wistar rats (n = 6 at each time point) received a single oral dose of 20 mg/kg racemic trans‐T. Blood samples were collected up to 12 h after drug administration. The kinetic disposition of trans‐T and M2 was enantioselective (AUC(+)/(−) ratio = 4.16 and 6.36, respectively). The direction and extent of enantioselectivity in the pharmacokinetics of trans‐T and M2 in rats were comparable to data previously reported for healthy volunteers, suggesting that rats are a suitable model for enantioselective studies of trans‐T pharmacokinetics. Chirality, 2011. © 2010 Wiley‐Liss, Inc. 相似文献
2.
Tramadol hydrochloride (TH), has become the most prescribed opioid worldwide. However, its neurotoxicity and abuse potential are not well documented. In the present study, TH administration induced abnormal behavior and body and brain mean weight loss. Two principal metabolites O- and N-desmethyltramadol were detected in the brain tissue, and N-desmethyltramadol was the main metabolite produced. A total of 30 differential protein spots were identified using semi-quantitative 2D-PAGE and proteomic analyses, and classified into 13 categories, in which subtypes of 14-3-3 proteins, creatine kinase, ATP synthase beta chain, and tubulin were identified at the separated location on the gels 3, 3, 4, and 11 times respectively. Many TH responsive proteins have functions related to oxidative stress, including 14-3-3 proteins, creatine kinase BB, ubiquitin carboxy-terminal hydrolase L-1, ATP synthase, synaptosome-associated protein, tubulin and actin. Irrespective of oxidative damage, other pathways affected include apoptosis, energy metabolism, signal disorders, and cytoskeletal structure. Ultrastructural observation of mitochondria showed a series of morphological changes in the case of TH exposure. 相似文献
3.
The objective of this work was to develop matrix sustained-release tablets of highly water-soluble tramadol HCl using natural
gums (xanthan [X gum] and guar [G gum]) as cost-effective, nontoxic, easily available, and suitable hydrophilic matrix systems
compared with the extensively investigated hydrophilic matrices (ie, hydroxypropyl methylcellulose [HPMC]/carboxymethyl cellulose
[CMC] with respect to in vitro drug release rate) and hydration rate of the polymers. Matrix tablets of tramadol (dose 100
mg) were produced by direct compression method. Different ratios, of 100∶0, 80∶20, 60∶40, 20∶80, 0∶100 of G gum (or X):HPMC,
X gum:G gum, and triple mixture of these polymers (G gum, X gum, HPMC) were applied. After evaluation of physical characteristics
of tablets, the dissolution test was, performed in the phosphate buffer media (pH 7.4) up to 8 hours. Tablets with only X
had the highest mean dissolution time (MDT), the least dissolution efficiency (DE8%), and released the drug following a zero-order model via swelling, diffusion, and erosion mechanisms. Guar gum alone could
not efficiently control the drug release, while X and all combinations of natural gums with HPMC could retard tramadol HCl
release. However, according to the similarity factor (f
2), pure HPMC and H8G2 were the most similar formulations to Topalgic-LP as the reference standard.
Published: March 17, 2006 相似文献
4.
Liver and kidney toxicity in chronic use of opioids: An experimental long term treatment model 总被引:2,自引:0,他引:2
In this study, histopathological and biochemical changes due to chronic usage of morphine or tramadol in liver and kidney
were assessed in rats. Thirty male Wistar rats (180–220 g) were included and divided into three groups. Normal saline (1 ml)
was given intraperitoneally as placebo in the control group (n = 10). Morphine group (n = 10) received morphine intraperitoneally at a dose of 4, 8, 10 mg/kg/day in the first, second and the third ten days of
the study, respectively. Tramadol group (n = 10), received the drug intraperitoneally at doses of 20, 40 and 80 mg/kg/day in the first, second and the third ten days
of the study, respectively. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH),
creatinin, blood urea nitrogen (BUN) and malondialdehyde (MDA) levels were measured in the serum. Liver and kidney specimens
were evaluated by light microscopy. Serum ALT, AST, LDH, BUN and creatinin levels were significantly higher in morphine group
compared to the control group. Serum LDH, BUN and creatinin levels were significantly increased in the morphine group compared
to the tramadol group. The mean MDA level was significantly higher in morphine group compared to the tramadol and control
groups (P<0.05). Light microscopy revealed severe centrolobular congestion and focal necrosis in the liver of morphine and
tramadol groups, but perivenular necrosis was present only in the morphine group. The main histopathologic finding was vacuolization
in tubular cells in morphine and tramadol groups. Our findings pointed out the risk of increased lipid peroxidation, hepatic
and renal damage due to long term use of opioids, especially morphine. Although opioids are reported to be effective in pain
management, their toxic effects should be kept in mind during chronic usage
Presented at the 10th XX Annual ESRA Congress, 6–9 April 2002, Warsaw, Poland. 相似文献
5.
In experiments on albino male mice weighing 24 to 32 g, we studied the suppression of the pain reaction induced by injection
of formalin into the dorsal surface of the foot, using a combination of injection of tramadol hydrochloride (Tramal) in a
dose of 0.42 mg/kg and irradiation of the acupuncture point (AP) E-36 with low-intensity microwaves (frequency 30 to 300 GHz
and power rate density 3·10−9 W/cm2). The combined use of tramadol injection and the action of microwaves on the AP led to a decrease in the duration of the
pain reaction (licking of the pain nidus), on average, by 58.2%, as compared with that in the control animal group. The analgesic
effect was more strong in the case of such a combination than after isolated injection of tramadol in doses of 0.83 and 0.42
mg/kg (by 14.4 and by 10.0%, respectively) and isolated microwave irradiation of the AP TA E-36 (by 48.7%). The data obtained
demonstrate the possibility of effective analgesia using a combination of microwave irradiation of the AP and the pharmacological
influence with a significant decrease in the dose of the analgesic.
Neirofiziologiya/Neurophysiology, Vol. 38, No. 4, pp. 314–319, July–August, 2006. 相似文献
6.
Curticapean A Muntean D Curticapean M Dogaru M Vari C 《Journal of biochemical and biophysical methods》2008,70(6):1304-1312
The optimized method for HPLC determination of tramadol and its metabolite O-desmethyl tramadol in human plasma using sotalol as internal standard has been developed and validated by a new approach. The determination by fluorescence detection was performed on re-eluted solution, obtained after liquid–liquid extraction with ethyl acetate of the three analytes from plasma. The chromatographic separation of tramadol under a gradient elution was achieved at a temperature of 15 °C with a RP-18 column, guarded by a C18 precolumn. The mobile phase was a mixed aqueous solution containing ortho-phosphoric acid, triethylamine, acetonitrile and methanol in a complex gradient mode. The quantitative determination of tramadol was performed at different successive pairs of excitation/emission wavelengths (200/300 nm, 200/295 nm, 212/305 nm) with lower limits of quantification: LLOQ = 4.078 ng/ml for tramadol, respectively LLOQ = 3.271 ng/ml for O-desmethyl tramadol. For the LLOQ limits, were calculated the values of the coefficient of variation and difference between mean and the nominal concentration. For tramadol analyte they were CV% = 5.147% and bias% = − 7.273% in the intra-days and CV% = 4.894% and bias% = 0.836% in the between-days assay, respectively for the metabolite O-desmethyl tramadol they were CV% = 11.517% and bias% = 0.337% in the intra-days and CV% = 6.41% and bias% = 3.259% in the between-days assay.
In addition, the stabilities of the analytes were verified in different conditions. Both, tramadol and its metabolite proved to be stable in plasma for four weeks, frozen at − 20 °C, but also for 48 h at 15 °C in the re-eluted solution after liquid–liquid extraction. 相似文献
7.
本文旨在研究曲马朵(tramadol,TRA)和二氢埃托啡(dihydroetorphine,DHE)联合用药是否可产生协同镇痛并延缓耐受的发生。TRA(mg,腹腔注射)与DHE(ng,皮下注射)按固定比率给药(1:6.25,1:12.5,1:25,1:50,l:100,1:200),用热辐射甩尾法评价镇痛效应,采用等高线法评估药物的协同作用。在急性耐受实验中,连续6次注射TRA(20mg/kg)、DHE(1000ng/kg)或两药的组合(TRA20mg/kg+DHE250ng/kg)。结果显示:(1)除1mg:6.25ng和1mg:50ng两个比例外,其他所有比例用药均产生显著的协同镇痛效应;(2)TRA与DHE联合用药的疗效在连续给药中持续时间明显延长,提示二者联合使用可延缓耐受。以上结果提示:TRA与DHE在一定剂量比范围内可产生协同镇痛效应,并可推迟耐受的形成。 相似文献
8.
Management of moderate or severe chronic pain conditions is the burden of clinicians dealing with patients trying to improve their quality of life and diminish their suffering. Although not a new opioid, tramadol has been recently rediscovered and widely used; this may be due to its favorable chronic safety and dependence profiles together with its high potency. Tramadol is a centrally acting analgesic with half-life of ~6 h; therefore, it requires frequent dosing. It is freely soluble in water; hence, judicious selection of retarding formulations is necessary. The current study is focused on the innovation of a novel, simple, monolayer, easy-to-use, cost-effective, and aesthetically acceptable bioadhesive transdermal delivery system overcoming the defects of the conventional “patch” as carrier system for tramadol, ensuring its adequate delivery, along with the physicochemical evaluation of the designed formulations. Monolithic tramadol matrix films of chitosan, different types of Eudragit®, and binary mixtures of both were prepared. As a single-polymer film, chitosan film showed best properties except for somewhat high moisture uptake capacity, insufficient strength and rapid release, and permeation. Polymer blends were monitored in order to optimize both properties and performance. Promising results were obtained, with chitosan–Eudragit® NE30D (1:1) film showing the most desirable combined, sufficiently rapid as well as prolonged release and permeation profiles along with satisfactory organoleptic and physicochemical properties. 相似文献
9.
In the present investigation, a quality by design (QbD) strategy was successfully applied to the fabrication of chitosan-coated nanoliposomes (CH-NLPs) encapsulating a hydrophilic drug. The effects of the processing variables on the particle size, encapsulation efficiency (%EE) and coating efficiency (%CE) of CH-NLPs (prepared using a modified ethanol injection method) were investigated. The concentrations of lipid, cholesterol, drug and chitosan; stirring speed, sonication time; organic:aqueous phase ratio; and temperature were identified as the key factors after risk analysis for conducting a screening design study. A separate study was designed to investigate the robustness of the predicted design space. The particle size, %EE and %CE of the optimized CH-NLPs were 111.3?nm, 33.4% and 35.2%, respectively. The observed responses were in accordance with the predicted response, which confirms the suitability and robustness of the design space for CH-NLP formulation. In conclusion, optimization of the selected key variables will help minimize the problems related to size, %EE and %CE that are generally encountered when scaling up processes for NLP formulations. The robustness of the design space will help minimize both intra-batch and inter-batch variations, which are quite common in the pharmaceutical industry. 相似文献
10.
By using a high-performance capillary electrophoresis method, the pharmacokinetics of the enantiomers of trans-tramadol (trans-T) and its active metabolite, trans-O-demethyltramadol (M1), was studied in healthy male and female Chinese volunteers after oral administration of 100 mg trans-T hydrochloride. The values of Cmax for the enantiomers of trans-T and M1, and AUC0- infinity for (-)-trans T, (+)-M1, and (-)-M1 were higher in females than in males. The values of V(d)/F for the enantiomers of trans-T and CLr for (+)-M1 were lower in females than in males. The value of t(1/2) for (-)-M1 was longer in females than in males. There were significant differences in pharmacokinetic parameters of the two enantiomers of trans-T or M1 both in males and in females. The (+)/(-)-enantiomeric ratios of t(max), V(d)/F for trans-T in males were significantly different from those in females and the (+)/(-)-enantiomeric ratios of pharmacokinetic parameters for M1 in males were similar to those in females. There are gender-related differences in the pharmacokinetics of the enantiomers of trans-T and M1 which may be due to the greater body weights for men and/or the higher CYP2D6 activity in women. The pharmacokinetics of trans-T and M1 is stereoselective in men and women. There is a gender-related difference in the stereoselectivity in pharmacokinetics of trans-T in human and the stereoselectivity in pharmacokinetics of M1 in men is similar to that in women. Chirality 16:112-118, 2004. 相似文献