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1.
The single-pass intestinal perfusion technique has been used extensively to estimate the wall permeability in rats. The unbiased membrane parameters can be obtained only when the aqueous resistance is properly accounted for. This aqueous resistance was calculated numerically from a convective diffusive mass transfer model, including both passive and carrier-mediated transport at the intestinal wall. The aqueous diffusion layer resistance was shown to be best described by a function of the form, where G z , P* m P* c K m and C o are, respectively, Graetz number, passive permeability, carrier-mediated permeability, Michaelis constant, and the drug concentration entering the tube. Asterisked are dimensionless quantities obtained by multiplying the permeability constants with R/D, where R and D being radius and drug diffusivity, respectively. A, B, C, D and E were obtained by a least-squares nonlinear regression method, giving values of 1.05, 1.74, 1.27, 0.0659, and 0.377, respectively, over the range of 0.001 G z 0.5, 0.01 P* m 10, 0.01 P* c 10, and 0.01 K m /C o 100. This aqueous resistance was found to converge to those calculated from Levich's boundary layer solution in low Graetz range, indicating the correct theoretical limit. Using an iteration method, the equation was shown to be useful in extracting the intrinsic membrane permeability from the experimental data.  相似文献   

2.
Summary The relative inotropic and chronotropic activity of -adrenoceptor agonists was studied in the noradrenaline-depleted, anaesthetized cat. Terbutaline, a selective 2-adrenoceptor agonist, gave at a certain dose a more pronounced chronotropic than inotropic response, while a new 1-selective adrenoceptor agonist (–)-H 80/62 produced the same degree of chronotropic and inotropic stimulation. The results indicate that there is some difference between the -adrenoceptors in the sinus node mediating chronotropic stimulation and -adrenoceptors in the ventricular myocardium mediating stimulation of the contractile force. It has been shown that there are both 1- and 2-adrenoceptors in the heart (Carlsson et al., 1972). In the light of this finding it is hypothetized that there are differences in the relative distribution of 1- and 2-adrenoceptors in the sinus node and in the myocardium. Although 1 is the predominant type of -adrenoceptor in both regions, the 1: 2 concentration ratio seems to be higher in the myo-cardium, than in the sinus node.  相似文献   

3.
Four antagonists were examined for their ability to differentiate 2A from the orthologous 2Dadrenoceptors. The antagonists were (2S,12bS) 1, 3-di-methylspiro(1, 3, 4, 5, 6, 6, 7,12b-octahydro-2H-benzo[b]furo[2,3-a]quinolizine)-2,4-pyrimidin-2-one (MK 912), 2-[2-(methoxy-1, 4-benzodioxanyl)imidazoline (RX 821002), efaroxan and benoxathian. The 2-autoreceptors in rabbit brain cortex were chosen as 2A- and the a2-autoreceptors in guinea-pig brain cortex as 2D-adrenoceptors. Slices of the brain cortex were preincubated with 3H-noradrenaline and then superfused and stimulated electrically by brief pulse trains (4 pulses, 100 Hz) that led to little, if any, 2-autoinhibition. 5-Bromo-6-(2-imidazolin-2-ylamino)quinoxaline (UK 14,304) was used as an 2-adrenoceptor agonist.UK 14, 304 decreased the stimulation-evoked overflow of tritium. The antagonists shifted the concentration-inhibition curve of UK 14, 304 to the right in an apparently competitive manner. Dissociation constants of the antagonists were calculated from the shifts. MK 912, RX 821002 and efaroxan had markedly higher affinity for (guinea-pig) 2D-adrenoceptors (pK d values 10.0, 9.7 and 9.1, respectively) than for (rabbit) 2A-adrenoceptors (pK d 8.9, 8.2 and 7.6, respectively). Benoxathian had higher affinity for 2A- (pK d 7.4) than for 2D-adrenoceptors (pK d 6.9). Ratios calculated from the K d values of the four compounds differentiated between 2A and 2D up to 100 fold. It is concluded that MK 912, RX 821002, efaroxan and benoxathian are antagonists with high power to differentiate 2A- from 2D-adrenoceptors.  相似文献   

4.
Recombinant human transforming growth factor beta (rhTGF-1) enhances the healing process after topical application to various animal wound models. A detailed pharmacokinetic and tissue distribution study was performed to support the clinical development of rhTGF-1 for wound healing indications. Rats received radioiodinated or unlabeled rhTGF-1 as an intravenous (iv) bolus or as a topical formulation applied to a full thickness wound. Plasma concentrations of TGF-1 were estimated from TCA-precipitable radioactivity or were measured by ELISA. Following iv administration, the initial half-life was rapid (<11 min), regardless of whether radi-olabeled or unlabeled rhTGF-1 was used. The terminal half-life was long (163 min) when the test material was radioiodinated and administered as a trace dose and relatively short (61 min) when given at high doses and assayed by ELISA. Analysis of plasma radioactivity by SDS-PAGE revealed a time-dependent clearance of the 25-kDa parent molecule without a significant appearance of lower molecular weight radiolabeled metabolites. The majority of the radioactivity was associated with highly perfused organs, known iodide elimination pathways, and the thyroid at 1 and 8 hr after iv injection. After topical administration of a high dose (0.8 mg/kg), no immunoreactive TGF-1 was detectable in plasma samples taken over a 48-hr period. However, trace amounts (0.05 ng/mL) of acid-precipitable radioactivity were detected in plasma after topical application of [125I]rhTGF-1 (1 µg/kg, 126 µCi/kg). A significant portion (35%) of the [125I]rhTGF-1 persisted intact (25 kDa) at the wound site 24 hr after application. In conclusion, rhTGF-1 was rapidly cleared after iv bolus administration and distributed primarily to the liver, lungs, kidney, and spleen. Little systemic exposure was observed after applying a single topical dose of rhTGF-1 to a wound, and the intact molecule persisted at the wound site.  相似文献   

5.
Summary The effects of p-tyramine and p-octopamine on the twitch responses of the prostatic portion of the rat vas deferens to electrical stimulation (0.025 Hz) were compared with the effects of noradrenaline. In tissues with normal monoamine oxidase (MAO) activity, the three amines increased the height and duration of the twitch contractions. When MAO activity was inhibited by pargyline (10 mol/l), p-tyramine and p-octopamine had mixed excitatory-inhibitory effects on the twitches, while noradrenaline had mostly excitatory effects along the whole range of concentrations assayed (0.158–15.8 mol/l). Selective blockade of 1- and 2-adrenoceptors, by corynanthine and yohimbine, respectively, showed that the excitatory effect of the amines depended on the activation of 1-adrenoceptor and that the inhibitory action was related to the activation of 2-adrenoceptors. Pretreatment with reserpine (5 mg/kg, 24 h; 2.5 mg/kg, 2 h before the experiment) largely prevented the effects of p-tyramine and p-octopamine, but the amines still modified the twitch responses to field stimulation. The addition of corynanthine and yohimbine to the bathing fluid revealed a considerable activation of 1-excitatory and 2-inhibitory adrenoceptors. Cocaine (10 mol/l) did not antagonize, but rather enhanced the inhibitory effects of p-tyramine and p-octopamine in tissues with normal contents of noradrenaline. Moreover, cocaine did not antagonize the inhibition caused by p-tyramine, and enhanced the inhibition induced by p-octopamine in the prostatic portion of the vasa deferentia from reserpine-pretreated animals. These results suggest that in this tissue, at least when MAO activity is inhibited, p-tyramine and p-octopamine behave similarly. The effects of both amines on the twitch contractions depend on the noradrenaline-releasing action of the compounds and, in addition, the compounds seem to activate adrenoceptors directly. Send offprint requests to S. M. Celuch at the above addressCareer Investigator on leave of absence from the Consejo de Investigaciones Científicas y Técnicas, ININFA, Junín 956, 5°P, RA-1113 Buenos Aires, Argentina  相似文献   

6.
The purpose of this investigation was to develop an in vitro pharmacodynamic model (IVPM) that would simultaneously simulate in vivo serum and middle ear amoxicillin pharmacokinetic characteristics of acute (purulent) otitis media and then utilize the IVPM to assess amoxicillin-mediated killing of a type 7F Streptococcus pneu-moniae (MIC = 0.002 mg/L). The IVPM consisted of a sterile central compartment and a membrane-bound infected peripheral compartment. Peak peripheral compartment amoxicillin concentrations occurred within 2 hr after its introduction into the central compartment and were approximately 30% of peak central compartment concentrations. Amoxicillin elimination from the central compartment was designed to provide a 1-hr t 1/2. Amoxicillin elimination from the peripheral compartment was slower than from the central compartment, with an average half-life of 2.3 hr. Significant concentration-related differences in maximal bacterial kill rates were not detected over the range of amoxicillin concentrations studied (0.26 to 14.6 mg/L). However, at peak central compartment amoxicillin concentrations of 2 mg/L, a lag phase in killing was observed. In general, the in vitro pharmacokinetic data derived from this model compare well with published in vivo data.  相似文献   

7.
The permeation enhancing property of 5% oleic acid in ethanol on -estradiol was investigated in vitro and in vivo using symmetrical and asymmetrical side-by-side diffusion cells and the human skin sandwich flap, respectively. -Estradiol permeability in vitro and in vivo was similar in 75% ethanol (ETOH). Oleic acid (5%) did not alter -estradiol permeability in vivo but increased permeability sixfold in vitro in symmetrical diffusion cells. -Estradiol permeability in oleic acid was not different from that in ETOH, however, using asymmetrical diffusion cells. Stratum corneum-to-vehicle partition coefficients of -estradiol in the vehicles were similar, yet fourfold more steroid was detected in skin biopsies from the in vitro symmetrical diffusion cells. Thus, oleic acid increased -estradiol permeability in vitro only when skin was equilibrated with fatty acid. Attention to in vitro diffusion cell design and its relevance in vivo is critical to defining the mechanisms of enhanced solute permeation.  相似文献   

8.
Summary This study describes a depolarizing action of 5-hydroxytryptamine (5-HT) on rabbit isolated preganglionic cervical sympathetic nerves using an extracellular recording technique. From cumulative concentration-response curves for 5-HT (1 mol/1-1 mmol/1), the mean maximal depolarization was shown to be 277 ± 32 V and EC50 was 9.4 mol/l(6.5–13.6 mol/l, geometric mean, 95% confidence limits, n = 42). The responses to 5-HT displayed marked tachyphylaxis. When cumulative concentration-response curves to 5-HT and 2-methyl-5-HT were determined in the same preparations (n = 4), the mean maximal response to 5-HT was 519 ± 167 V, EC50 32.2 mol/l (8.8–118 mol/l) and the mean maximal response to 2-methyl-5-HT was 317 ± 63 V, EC50 35.1 mol/l (12.9–95.5 mol/l, geometric means, 95 % confidence limits). The action of selective 5-HT antagonists was tested on repeated cumulative concentration-response curves to 5-HT. Neither methiothepin (0.1–1 mol/l, n = 3) nor ketanserin (0.1–1 mol/l, n = 3) had an action on 5-HT responses. The selective 5-HT3 antagonists MDL 72222, ICS 205-930 and SDZ 206–830 were all potent antagonists of the 5-HT depolarizations. The action of these antagonists was quantified by determining the apparent pA2 from the dose ratios and a Schild plot. For MDL 72222 (1 nmol/1-0.1 mol/l), the apparent pA2 was 9.1 ± 0.1 (n = 12), Schild plot: 9.2; for ICS 205–930 (0.1 nmol/l–3 nmol/1), the apparent pA2 was 10.4 ± 0.1 (n = 11), Schild plot 10.3, and for SDZ 206–830 (0.03 nmol/l-1 nmol/1), the apparent pA2 was 11.2 ± 0.1 (n = 12), Schild plot 11.2. 5-HT depolarizations were unaffected by hexamethonium (0.5 mmol/1). 5-HT depolarizations were reduced by superfusion with both Na-free (42 ± 8% of controls, n = 4) and Na/Ca-free media (35 ± 7% of controls, n = 4). It is concluded that 5-HT depolarizations of rabbit preganglionic cervical sympathetic nerve are mediated by 5-HT3 receptors. The data with selective 5-HT3 receptor antagonists suggest that the receptor profile may be more like that for the 5-HT3 receptor on the terminals of sympathetic nerves than that for the 5-HT3 receptor on the soma of superior cervical ganglion cells or on vagal afferent neurones. Send offprint requests to D. I. Wallis at the above address  相似文献   

9.
Purpose. This study determines comparative bioavailability of diclofenac sodium lotion compared to an aqueous solution after topical application to viable human skin in vitro. In addition, the difference between a single dose and multiple doses (8 times) was also determined. Methods. An in vitro flow-through diffusion cell system was employed, using radiolabelled diclofenac sodium. Results. Multiple doses of lotion (2 l/cm2 and 5 l/cm2) delivered a total of 40.1 ± 17.6 g and 85.6 ± 41.4 g diclofenac, respectively, at 48 h, compared to only 9.4 ± 2.9 g and 35.7 ± 19.0 g absorbed after topical application of diclofenac as an aqueous solution (P < 0.05). A single dose study showed no statistical difference between diclofenac delivered in lotion or an aqueous solution. Over 48 h the total absorption from lotion was 10.2 ± 6.7 g and 26.2 ± 17.6 g (2 l/cm2 and 5 l/cm2, respectively), compared to 8.3 ± 1.5 g and 12.5 ± 5.7 g from an aqueous solution. Both single doses of lotion and aqueous diclofenac showed decreased diclofenac absorption into the receptor fluid between 12 and 24 h. However, when applied multiple times, absorption from lotion was continually increasing up to 48 h. The total dose accountability ranged from 76.8 ± 8.2% to 110.6 ± 15.1% of the applied dose. Conclusions. Diclofenac lotion exhibited enhanced diclofenac percutaneous absorption rate through human skin (mass, flux and partition coefficient) when applied a multiple number of times and this enhanced absorption was maintained over 48 h. This suggests that a constituent of the lotion (DMSO) will enhance human skin absorption of diclofenac when used in a multi-dose regimen, but not after a single dose.  相似文献   

10.
Predicting Skin Permeability   总被引:16,自引:0,他引:16  
Published permeability coefficient (K p) data for the transport of a large group of compounds through mammalian epidermis were analyzed by a simple model based upon permeant size [molecular volume (MV) or molecular weight (MW)] and octanol/water partition coefficient (K oct). The analysis presented is a facile means to predict the percutaneous flux of pharmacological and toxic compounds solely on the basis of their physicochemical properties. Furthermore, the derived parameters of the model have assignable biophysical significance, and they provide insight into the mechanism of molecular transport through the stratum corneum (SC). For the very diverse group of chemicals considered, the results demonstrate that SC intercellular lipid properties alone are sufficient to account for the dependence of K p upon MV (or MW) and K oct. It is found that the existence of an aqueous-polar (pore) pathway across the SC is not necessary to explain the K p values of small, polar nonelectrolytes. Rather, their small size, and consequently high diffusivity, accounts for their apparently larger-than-expected K p. Finally, despite the size and breadth of the data set (more than 90 compounds with MW ranging from 18 to >750, and log K oct ranging from –3 to + 6), the postulated upper limiting value of K p for permeants of very high lipophilicity cannot be determined. However, the analysis is able to define the physicochemical characteristics of molecules which should exhibit these maximal K p values. Overall, then, we present a facile interpretation of a considerable body of skin permeability measurements that (a) very adequately describes the dependence of K p upon permeant size and lipophilicity, (b) generates parameters of considerable physicochemical and mechanistic relevance, and (c) implies that the SC lipids alone can fully characterize the barrier properties of mammalian skin.  相似文献   

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