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OBJECTIVE： To compare the quality of original preparations of Thioctic acid injection and generic preparations from 2 domestic manufacturers， discuss the acute toxicity test of mice and to investigate the project of consistency evaluation methods. METHODS： According to the quality standard that stated in Chinese Pharmacopeia， physicochemical properties （characters， pH， osmotic pressure， etc.， contents and related substances of samples of Thioctic acid injection as well as LD50 in acute toxicity test （n＝10）， and mortality of mice after administration of injection solution （n＝30） were compared among 3 manufacturers. RESULTS： The physicochemical properties as and related substances of the original drug and 2 generic drugs were all in line with the quality standard； the contents of 3 samples ranged 95％-105％. The acute toxicity test results showed that the LD50 values of 2 generic drugs （LD50： 247.911 mg/kg， 95％ confidence interval： 222.209-277.999 mg/kg；LD50： 215.291 mg/kg， 95％ confidence interval： 196.637-235.053 mg/kg） were smaller than that of original drug （LD50： 266.534 mg/kg， 95％ confidence interval： 250.597-283.418 mg/kg）， but there was no statistical difference （P＞0.05）. The results of 3 repeated experiments showed that there was statistical significance in the number of animal death caused by the 2 generic drugs （26， 28） was more than that of the original drug （19） （all P＜0.05）， when injection solution was injected into mice in a single dose. After administration of the original drug， mice showed excitatory reactions such as movement and squeal， while 2 generic drugs showed inhibitory reactions. CONCLUSIONS： 2 generic drugs of Thioctic acid injection and the original drug all conform to the relevant regulations of Chinese Pharmacopoeia in terms of preparation quality standards， but the results of acute toxicity test are quite different， so it is difficult to prove the consistency between the 2 generic drugs and the original drug. Therefore， acute toxicity test is necessary for the consistency evaluation of injections.
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Aim To investigate the selective inhibition of ethanol on muscarinic receptor-or 5-HT receptor-me-diated contractile responses in the circular smooth mus-cle strips isolated from the different regions of rat stom-ach. Methods Circular muscle strips isolated from the rat gastric fundus, body, cardia and pylorus were prepared, and the contractile responses to carbachol ( CCh ) or 5-HT were recorded. Results Ethanol (0. 000 05~0. 000 5, V/V) did not affect the contrac-tile response to CCh in circular muscle strips from the rat gastric fundus and cardia, and that to 5-HT in the strips from rat gastric fundus and body ( P >0. 05 ) . However, ethanol(0. 000 1 and 0. 000 5) significantly inhibited the Emax value of the contraction by CCh from (12. 18 ± 0. 33) g of control level to (10. 88 ± 0. 41) g and -lgEC50 value from ( 6. 33 ± 0. 05 ) of control level to (6. 12 ± 0. 06)(P <0. 05) in the strips from rat gastric body. Ethanol(0. 000 1 and 0. 000 5) also significantly inhibited the Emax value of the contraction by CCh from (2. 87 ± 0. 15) g of control level to (2. 2 ± 0. 13) g and -lgEC50 value from (6. 49 ± 0. 10) of control level to (6. 05 ± 0. 09)(P<0. 01) in the strips from rat gastric pylorus. Moreover, ethanol ( 0. 000 1 and 0. 000 5) significantly inhibited the Emax value of the contraction by 5-HT from (2. 93 ± 0. 35) g of con-trol level to ( 2. 1 ± 0. 30 ) g ( P<0. 05 ) , but did not affect the -lgEC50 value in the strips from rat gastric cardia. Conclusions Ethanol inhibits the contractile responses to 5-HT only in the circular muscle strips of rat gastric cardia, and it inhibits the contractile respon-ses to CCh more strongly in the circular muscle strips of gastric pylorus than gastric body. In those gastric circular muscle strips, ethanol decreases both the ac-tivity and affinity of CCh to muscarinic receptors, but decreases only the activity of 5-HT to its receptors.
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Aim To investigate the role of endothe-lium in the enhancement of phenylephrine-mediated vasoconstriction by bupivacaine in the isolated rat aor-ta.Methods The isolated rat aortic rings were pre-pared, and the vascular endothelium was removed chemically or physically .Phenylephrine-mediated vas-oconstriction was recorded .Results A pretreatment with bupivacaine at 30 μmol · L-1 for 20 min signifi-cantly increased the Emax value of vasoconstrictive re-sponses to phenylephrine from 2.22 ±0.07 g of sol-vent-controlled group to 2.50 ±0.05 g ( P0.05 ) .A pretreatment with bupivacaine at 30 μmol · L-1 for 20 min slightly but significantly inhibited the vasoconstrictive responses to low concen-tration of phenylephrine in the isolated endothelium-de-nuded rat aorta (P0.05 ) .Conclusion Bupivacaine enhances α1-adre-noceptor-mediated vasoconstriction by inhibiting vascu-lar endothelium in the isolated endothelium-intact rat aorta, Which potentiates indirectly the vasoconstrictive responses to phenylephrine .
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Aim To study the mechanisms of inotropic responses to doxazosin enantiomers in the isolated rat atrium.Methods We analyzed the positive inotropic response to (-)doxazosin and the negative inotropic response to (+)doxazosin in the left atrium of rat u-sing receptor-pharmacological technique.Results In the preparation treated with verapamil,the positive in-otropic responses to 3 μmol·L-1 (-)doxazosin were significantly inhibited from the control level (245.7 1 ± 44.29)mg to (172.50 ±43.34)mg,(P<0.05).In the preparation treated with methylene blue,the posi-tive inotropic responses to 3 μmol·L-1 (-)doxazosin were significantly potentiated from the control level (245.7 1 ±44.29 )mg to (303.33 ±45 .90 )mg,(P<0.05 ).In the preparation treated with H-89 ,the positive inotropic responses to 3,10 and 30 μmol · L-1 (-)doxazosin were (338.57 ±96.86 ) mg, (471.43 ±107.61)mg and (520.00 ±103.44)mg, which were significantly (P<0.05 ~0.01)larger than the control levels of (245.71 ±44.29)mg,(314.29 ±90.34)mg and (357.14 ±68.49 )mg.Treatment with phenoxybenzamine,atropine,propranolol or indo-methacin did not significantly affect the responses to doxazosin enantiomers.Conclusion The positive ino-tropic responses to (-)doxazosin in the isolated left a-trium of rat are partially involved in L-type Ca2+chan-nels and intracellular cGMP level.However,α-adre-noceptors,muscarinic receptors,β-adrenoceptors and cyclooxygenases are not related to the responses to doxazosin enantiomers.
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OBJECTlVE To investigate the effect of stretch on muscarinic receptor- and 5-hydroxytryptamine( 5-HT)receptor-mediated contractiIe responses in isoIated circuIar muscIe strips taken from the rat stomach. METHODS The contractiIe responses to carbachoI(CCh)0.001-30 μmoI·L-1 or 5-HT 0.0001 -30 μmoI·L-1 administered cumuIativeIy were recorded in isoIated circuIar muscIe strips taken from the gastric fundus,body,cardia and pyIorus of rats under different preIoads of 1.0,1.5,2.0, 2.5 and 3. 0 g,but a singIe concentration of CCh 0. 3 μmoI·L-1 was administered to the antrum. RESULTS The -Log EC50 vaIue for CCh in the isoIated circuIar muscIe strips of the gastric fundus, body and pyIorus under 1.0 g preIoad was the Iargest,but decreased significantIy with higher preIoads (P﹤0.05,P﹤0.01). A simiIar resuIt was obtained in the isoIated circuIar muscIe strips of the gastric body when 5-HT was used as an agonist. The Emax vaIue of contractiIe responses to CCh and 5-HT in the cir-cuIar muscIe strips of the gastric cardia under 3.0 g preIoad was increased by 117.4% and 75.7% com-pared to that under 1.0 g preIoad. The Emax vaIue of contractiIe responses to 5-HT in the circuIar muscIe strips of the gastric body under 3.0 g preIoad was aIso increased by 115.9% when compared to 1.0 g preIoad. The Emax( g) vaIue of contractiIe responses to CCh in four types of muscIe strips was 10.453±2.956(cardia under 3.0 g preIoad),13.878±2.618(fundus under 2.5 g preIoad),10.244±1.843 (gastric body under 2.5 g preIoad)and 2.585±1.098(pyIorus under 2.5 g preIoad),respectiveIy. The Emax(g)vaIue of contractiIe responses to 5-HT in three types of muscIe strips was 4.363±1.705(cardia under 3.0 g preIoad),3.931±0.615(fundus under 3.0 g preIoad)and 3.161±0.680(gastric body under 3.0 g preIoad),respectiveIy. CONCLUSlON 0.5 g or 1.0 g preIoad is inadequate for accurate determi-nation of contractiIe responses mediated by muscarinic receptors and 5-HT receptors in isoIated circuIar muscIe strips taken from the rat gastric cardia,fundus,body and pyIorus,but 2.0 g preIoad is optimaI for investigating muscarine receptor- or 5-HT receptor-mediated contractiIe responses of isoIated gastric strips of rats.
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Aim To analyze the blocking effect of ( ± ) doxazosin [ ( ± ) DOX ] , ( -) doxazosin [ ( -) DOX] and ( +) doxazosin [( +) DOX] on the vaso-constriction of rat isolated mesenteric arterioles media-ted by α1-adrenoceptors. Methods The vasoconstric-tion induced by phenylephrine ( Phe) in the rat isola-ted mesenteric arterioles ( the second- and third-order branches) was recorded using DMT wire myograph sys-tem 620M, and theα1-adrenoceptor antagonistic activ-ity of ( ± ) DOX and its enantiomers was analyzed. Results The inner diameter of second- and third-or-der branches of the rat mesenteric artery was (162. 5 ± 5. 3) μm (n=11) and (103. 1 ± 2. 3) μm (n=23), respectively. The values of normalized preload of the second-and third-order branches, which were calculat-ed by the LabChart software, were (2. 93 ± 0. 51) mN ( n =11 ) and ( 2. 64 ± 0. 50 ) mN ( n =23 ) ( P >0. 05 ) . Vasoconstrictive responses to Phe in the sec-ond-order branche of rat mesenteric artery under nor-malized preloads were not significantly different from those under 5 mN preload;however, the Emax values of the Phe-induced vasoconstriction under 10 mN, 15 mN and 20 mN preloads were decreased by 12%, 29%and 43% ( P<0. 01 ) respectively compared with those under normalized preload. The concentration-response curves for Phe were shifted to right in a concentration dependent manner by ( -) DOX or ( +) DOX at 0. 001 , 0. 01 and 0. 1 μmol · L-1 without significant change in their Emax values in the second-and third-or-der branches of rat mesenteric artery. Schild plot anal-ysis indicated that ( -) DOX, ( +) DOX and ( ± ) DOX non-competitively inhibited the vasoconstrictive responses to Phe in the second-order branches, and the rank order of pKB values was ( +) DOX ( 8. 67 ± 0. 10 ) , ( ± ) DOX ( 8. 53 ± 0. 090 ) , ( -) DOX (7. 85 ± 0. 09). However, schild plot analysis indica-ted that ( -) DOX and ( +) DOX competitively inhibi-ted the vasoconstrictive responses for Phe in the third-order branch, and the rank order of their pKB values was ( ± ) DOX ( 8. 68 ± 0. 17 ) , ( +) DOX ( 8. 48 ± 0. 10 ) , ( -) DOX ( 7. 48 ± 0. 140 ) . Conclusion The α1-adrenoceptor blocking activity of ( -) DOX is much weaker than that of ( +) DOX or ( ± ) DOX in the rat isolated mesenteric arterioles, and there is a tendency to enhance the activity of ( ± ) DOX in third-order branches of the rat mesenteric artery though theα1-adrenoceptor blockade effect of ( ± ) DOX is not significantly different from ( +) DOX.
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Traditional medicine (herb medicine) began to prevail again over last two decades, and it is about 70% of the world population taking herb medicine as supplement or alternative medicine according to a recent survey. The consumption of herb medicine increased exponentially in Canada, Australia and Europe during last 10 years. Since concomitant administration of herbal and western medicine has become a trend, it requires paying close attention to the problem. Herb-drug interactions have been extensively investigated worldwide, and there is an increasing concern about the clinical herb-drug interaction. In this review we introduced the current progress in the herb-drug interactions including evidence-based clinical studies and establishment of levels of evidence for herb-drug interaction; and in the related mechanisms including the induction and inhibition of metabolic enzymes, inhibition and induction of transport and efflux proteins, alteration of gastrointestinal functions, and alteration in renal elimination. We also analyzed both the achievements and the challenges faced in the concomitant administration of traditional Chinese medicine and western medicine.
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The study is to establish an HPLC method using fluorescence detector for the determination of doxazosin enantiomers and investigate their chiral inversion in vitro and in vivo. Ultron ES-OVM was taken as the chiral chromatographic column, and the column temperature was 30 degrees C. Isocratic elution using a mobile phase of phosphate buffer-acetonitrile (85 : 15, v/v) at a flow rate of 0.8 mL x min(-1) was done. The fluorescence detection was set at lambda(Ex) = 255 nm and lambda(Em) = 385 nm. Prazosin was used as the internal standard. (-) Doxazosin or (+) doxazosin added into rat plasma in vitro was determined after incubating in 37 degrees C water bath for 2, 5 and 10 days. (-) Doxazosin or (+) doxazosin was administered orally to the rats for one months. Plasma samples were taken at 8 h after the last administration. A good linear relationship was achieved when the concentration of doxazosin enantiomers was within the range of 4 - 2 000 ng x mL(-1). The average recovery for (-) doxazosin was 99.5% with RSD 3.6%, and for (+) doxazosin was 99.3% with RSD 4.3%. Chiral inversion was observed neither in vitro nor in vivo studies. The method is selective, accurate and reproducible, which is suitable for the detection of doxazosin enantiomers in rat plasma. The in vitro and in vivo studies indicate that chiral inversion occurs uneasily between (-) doxazosin and (+) doxazosin in the rat.
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Objective To study the effects of adenosine triphosphate (ATP) on proliferation of human squamous esophageal carcinoma Eca-109 and hepatoma SMMC-7721 cells in vitro and the underlying mechanism. MethodsMTT assay was used to determine the proliferation of tumor cells. The AO/EB double stained cells were observed under fluorescence microscope. The effects of ATP on the cell cycle, apoptotic rate and apoptosis-related protein were detected by flow cytometry. Results ATP showed inhibitory effects on Eca-109 and SMMC-7721 cells at the concentration of 0.01～0.3 mmol/L. Exposure to 0.3 mmol/L ATP for 72 h, some of SMMC-7721 cells displayed morphological changes of apoptosis, but Eca-109 cells did not show the characteristics of apoptosis markedly. There was no significant change in the apoptotic rate and apoptosis-related protein of the two tumor cell lines treated with ATP 0.03, 0.1 and 0.3 mmol/L for 72 h respectively. The proportion of Eca-109 cells in G0/G1-phase of cellcycle was significantly increased, meanwhile the proportion of Eca-109 cells in S-phase and proliferation index value was significantly decreased by treatment with 0.3 mmol/L ATP. Conclusion ATP inhibited Eca-109 cell proliferation by changing the distribution of cell cycle phase, and its mechanism might not related to apoptosis, but for SMMC-7721 cell, the inhibition of cell proliferation induced by ATP was not related to the change in cell cycle.
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AIM Action of adenosine triphosphate(ATP)on longitudinal muscle strips of the rat distal colon has been reported, however, that of the rat proximal colon remains to be clarified. In this study we investigated the effects of ATP on longitudinal muscle strips isolated from the rat proximal colon and the receptors involved in the effects. METHODSIsometric relaxant and contractile responses to ATP (0.1 μmol · L- 1 - 1 mmol· L- 1 ) and adenosine (1 - 100 μmol· L-1) in longitudinal muscle strips of the rat proximal colon were observed. RESULTS ATP (0.1 μmol· L- 1 - 1 mmol· L- 1 ) produced a complicated response including an inhibition of rhythmic contraction and a weakly transient decrease in basic tone (0.05-0.08 g) followed by a concentration-dependent contraction (0.04- 0.44 g) in longitudinal muscle strips of the rat proximal colon at resting tension. Tetrodotoxin (0.1 μmol·L-1) did not influence the responses to ATP.Adenosine (1 - 100 μmol· L-1) did not produce an obvious contractile response in the preparation at resting tension. Concentration-dependent relaxant responses to ATP ( 1 μmol· L- 1 - 1 mmol· L- 1 ) in the preparation precon tracted with 5-hydroxytryptamine or with acetylcholine were 23.2％ - 94.6％ or 24.8 ％ - 92.4％, however the relaxant responses to adenosine were much weaker than those to ATP. CONCLUSION ATP produces contractileresponsesmainly via purine and pyrimidine (P) 2receptors and relaxant responses partially via P1 receptors in longitudinal muscle strips of the rat proximal colon.
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Aim To investigate the effects of ?,?-methylene ATP ( ?,?-MeATP) on the P2X1 purino-ceptor-mediated vasoconstriction by different administration ways in the rat mesenteric artery. Methods Isometric vasoconstrictive responses to ?,?-MeATP,administered in non-accumulative manner or single concentration manner,were recorded in the rat isolated mesenteric arterial rings. Results ?,?-MeATP ( 10 -7 ～ 10 -4 mol ? L -1 ) administered in both of the two manners produced concentration-dependent vasocon-strictive responses in the rat isolated mesenteric artery. The vasoconstrictive responses to ?,?-MeATP in single-concentration administration group were greater than those in non-accumulative administration group when the vasoconstriction was standardized either by tissue wet weight or by maximal response to 120 mmol ?L-1 KCl ( P
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Extracellular adenosine triphosphate (ATP) and adenosine are important signaling molecules in both intracellular and extracellular microenviroments of cells. They exert cytoxic and apoptotic effects in some tissues such as tumor. The proapoptotic mechanisms of adenosine and its receptors are involved in Adenylyl cyclase(AC), cAMP, Ca 2+ , etc. Apoptosis induced by ATP is as sociated with several purinergic receptors including P2X_1, P2X_2, P2X_7, P2Y_1, P2Y_2, et al, it is also involved in FasL/FasR, T cell receptor(TCR), and gene regulations of bcl-2 and bax.
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Aim To establish a model of biphasic vasoconstriction induced by electrical stimulation, and analyze effects of 1～100 nmol?L~(-1) tetrodotoxin (TTX) on the biphasic vasoconstriction in the ring preparation of the rabbit saphenous artery. Methods Isometric vasoconstriction of the rabbit saphenous arterial rings was recorded, and the sympathetic nerves of the arterial rings were activated with electrical stimulation. Results The biphasic neurogenic vasoconstriction was consistently induced by electrical stimulation (15 V,1 ms pulse duration,2～16 Hz for 32 s) in a frequency-related manner in the rabbit saphenous artery. TTX (3 nmol?L~(-1)),a neuronally selective sodium channel blocker,did not affect the first phase of vasoconstriction,but it markedly inhibited the second phase of vasoconstrictive responses to 2～16 Hz stimulation by 44 %～67 %. Increasing the concentration of TTX to 10 nmol?L~(-1), TTX inhibited the first phase of the vasocontractive responses to 4～16 Hz stimulation by 40%～57%,whereas it inhibited more than 90% of the second phase of vasoconstriction. Concentration-response curves for NA(0.01～30 ?mol?L~(-1)) were not affected by TTX (0.1 ?mol?L~(-1)), but the same concentration of TTX completely inhibited the biphasic vascular responses to electrical stimulation. The biphasic contractile responses to electrical stimulation were all abolished by guanethidine (10 ?mol?L~(-1)), but the vasoconstrictive responses to exogenous NA were not affected by it. Conclusion Biphasic vasoconstriction can be induced by electrical stimulation,and the first and the second phases of vasoconstriction are mediated by neurotransmitters released from sympathetic nerves in the rabbit isolated saphenous arterial ring preparation.
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AIM To study the growth inhibition of adenosine triphosphate (ATP) and adenosine (ADO) on cultured tumor cells in vitro. METHODS MTT assays were used to determine the inhibition of proliferation of ATP and ADO on several tumor cell lines, including human squamous esophageal carcinoma cells TE-13, human stomach carcinoma cells HGC-27 and human erythroleukemia cells K562. The morphological changes of ATP and ADO on the cell lines were observed under light microscope. RESULTS ATP and ADO produced a certain inhibition effect on TE-13, HGC-27, K562 cells at different concentration between 0.01～1.0 mmol?L -1. The maxium inhibition fraction of TE-13, HGC-27, K562 cells exposed to ATP for 72 h was 80.52%, 58.67% and 45.07%, respectively; and to ADO for 72 h, was 74.03%, 52% and 30.99%, respectively. Under light microscope, the tumor cells exposed to higher concentration(1 mmol?L -1) of ATP and ADO displayed morphological changes of apoptosis. CONCLUSION These results suggested that ATP has a certain cytotoxic effect on several tumor cell lines, it might partly be related to ADO. Its mechanism might involve apoptosis.
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This report indroduces the characterization of tetrodotoxin (TTX),and its pharmacological and clinical actions.
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ABSTRACT Calcium homeostasis is of crucial importance for the function of cardial myocytes in normal electrical and mechanical processes. The sarcoplasmic reticular Ca-ATPase and the sar-colemmic Na/Ca exchanger contribute mainly to the steady state of calcium in the myoplasm. The Na/Ca exchanger serves as the principal calcium extrusion mechanism and regulates calcium content of the sarcoplasmic reticulum by regulating the resting [Ca2+]i level, through which the Na/Ca exchanger regulates the force of contraction sequentially. Very small calcium entry can trigger significant sarcoplasmic reticular calcium release (CICR). During the upstroke and plateau phasesof the action potential, There is evidence that indicates Ca2+ influx via the Na/Ca exchanger, and the depolarisation-induced calcium entry on Na/Ca exchange may contribute mainly to triggering intra-cellular calcium release. Na/Ca exchange should be reevaluated as a route through which Ca2+, as a triggering signal, enters cardiac myocyte during excitation-contraction coupling.
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a adrenoceptor-mediated increases in smooth muscle tone of the prostate gland and urethra acts as a dynamic factor for BPH-related obstruction of the urethra, a1 adrenoceptor antagonists are considered as the first-line therapy for the patients with BPH. The search for selective a1A a-drenoceptor antogonists with high uroselectivity is strategical for drug discovery research.
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Object To study the effective portion in Cornus officinalis Sieb. et Zucc. extract (COE) for the treatment of arrhythmia. Methods Effect of COE on chloroform induced ventricular fibrillation in mice and electrophysiology of isolated guinea pig papillary muscle were studied. Results Antiarrhythmic effect of COE may be related to its prolongation of action potential duration, increase of the absolute value of resting potential and a decrease of autonomy of sinus node. The effective portion in COE may be its total organic acid and a certain yet unknown trace substance, whereas its total glycosides were devoid of such activities. Conclusion Pharmacodynamic and myocardial electrophysiologic studies showed that the total organic acid and a certain unknown trace substance possessed the obvious antiarrhythmic activity.
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Purines and pyrimidines have widespread and specific action in many tissues of both invertebrates and vertebrates. These compounds have powerful physiological roles in both short-term actions of neurotransmission, exocrine and endocrine secretion, and regulation of immune cell function,and long-term actions of cell growth, cell differentiation and proliferation in the development and regeneration.
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Aim To investigate the effect of racemic-doxazosin(rac-DOX),S-doxazosin(S-DOX) and R-doxazosin(R-DOX) on the proliferation of vascular smooth muscle cells(VSMCs) of the rat aorta.Methods VSMCs of the rat aorta were cultured,MTT assay was used to determine the cell proliferation and the morphological changes in VSMCs were analyzed using Giemsa's staining.Results The treatment with rac-DOX,S-DOX or R-DOX at 3~30 ?mol?L-1 for 96 h inhibited the proliferation of VSMCs significantly.However,the inhibitory effect of S-DOX on cell proliferation was more potent than that of R-DOX at the same concentration(P