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1.
Govender Thirumala Ehtezazi Touraj Stolnik Snjezana Illum Lisbeth Davis Stanley S. 《Pharmaceutical research》1999,16(7):1125-1131
Purpose. Due to the importance of drug-polymer interactions in, inter alia, drug loading/release, supramolecular assemblies and DNA delivery for gene therapy, the aim of this study was therefore to establish the mechanism of interaction between a model polymer (Polyacrylic acid, PAA) and a model drug (procaine HCl).
Methods. This was performed by studying the effect of salt (KCl) concentration on their heat released values using Isothermal Titration Microcalorimetry (ITM). The integrated released heat data were computer fitted to a one class binding model and the thermodynamic parameters (Kobs, H, and N) were determined.
Results. As the KC1 concentration was increased, Kobs decreased thus establishing the salt dependence of the interaction. The linear variation of Gobs with Sobs indicated that their interaction was entropically driven. The stoichiometry of the interaction was calculated to be one procaine molecule per monomer of PAA. Dissection of the total observed free energy at each KC1 concentration indicated that the contribution of the non-electrostatic attractions to the interaction of PAA with procaine HC1 was greater than those of the electrostatic attractions.
Conclusions. We have shown that the interaction between PAA and procaine HC1 is dependent upon the presence of counterions (monovalent ions) and is mainly entropically driven. The calculated stoichiometry indicated that one procaine HC1 molecule neutralised one carboxylic acid group on PAA. Although electrostatic interactions were necessary for initiating complex formation, the non-electrostatic forces were dominant in stabilising the PAA-procaine HC1 complex. 相似文献
2.
Purpose. To investigate the solution process of drug substances (exemplified by benzoic acid, BA, and acetylsalicylic acid, ASA), particularly the interrelation between enthalpic and entropic terms of Gibbs energy, in different solvents. To develop an approach for the estimation of standard solution enthalpies based on a self-consistent thermochemical scale.
Method. Two independent methods, solubility experiments (concentrations of saturated solutions) and solution calorimetry (standard solution enthalpies) in aliphatic alcohols and individual organic solvents were used. Correlation between the thermodynamic functions in various solvents were analyzed by standard statistical methods. Multiple regression analysis between H
0
sol values and the parameters of the solvents was run on the Koppel-Palm equation.
Results. Based on experimental data, a compensation effect between thermodynamic functions was observed. Correlation was found between H
0
sol (BA) and H
0
sol (ASA) [where the H
0
sol (BA)-values were used as a self-consistent thermochemical scale]. Furthermore, H
0
sol correlated with the Koppel-Palm basicity of the solvents.
Conclusions. The model based on solubility and solution experiments might be useful for the prediction of solubility or solvation of drug substances in different media. The regression equation based on the self-consistent thermochemical scale makes it possible to approximate the ability to solvate a drug substance in comparison with structure-relative substances. 相似文献
3.
Purpose. To study the partitioning of model acids ((RS)-warfarin and salicylic acid), and bases (lidocaine, (RS)-propranolol and diazepam), with immobilized artificial membrane (lAM)-HPLC, as compared to partitioning in the standardized phosphatidylcholine liposome/buffer system.
Methods. The pH-dependent apparent partition coefficients D were calculated from capacity factors (kIAM) obtained by IAM-HPLC, using a 11-carboxylundecylphosphocholine column. For lipophilic compounds kIAM, values were determined with organic modifiers and extrapolation to 100% water phase (kIAMw) was optimized. Temperature dependence was explored (23 to 45° C), and Gibbs free energy (G), partial molar enthalpy (H) and change in entropy (S) were calculated. Equilibrium dialysis was used for the partitioning studies with the liposome/buffer system.
Results. For extrapolation of kIAMw, linear plots were obtained both with the respective dielectric constants and the mole fractions of the organic modifier. All tested compounds showed a similar pH-D diagram in both systems; however, significant differences were reproducibly found in the pH range of 5 to 8. In all cases, G and H were negative, whereas S values were negative for acids and positive for bases.
Conclusions. In both partitioning systems, D values decreased significantly with the change from the neutral to the charged ionization state of the solute. The differences found under physiological conditions, i.e. around pH 7.4, were attributed to nonspecific interactions of the drug with the silica surface of the IAM column. 相似文献
4.
Purpose. Calculation of the ideal solubility of a crystalline solute in a liquid solvent requires knowledge of the difference in the molar heat capacity at constant pressure of the solid and the supercooled liquid forms of the solute, Cp. Since this parameter is not usually known, two assumptions have been used to simplify the expression. The first is that Cp can be considered equal to zero; the alternate assumption is that the molar entropy of fusion, Sf, is an estimate of Cp. Reports claiming the superiority of one assumption over the other, on the basis of calculations done using experimentally determined parameters, have appeared in the literature. The validity of the assumptions in predicting the ideal solubility of five structurally unrelated compounds of pharmaceutical interest, with melting points in the range 420 to 470K, was evaluated in this study.
Methods. Solid and liquid heat capacities of each compound near its melting point were determined using differential scanning calorimetry. Linear equations describing the heat capacities were extrapolated to the melting point to generate the differential molar heat capacity.
Results. Linear data were obtained for both crystal and liquid heat capacities of sample and test compounds. For each sample, ideal solubility at 298K was calculated and compared to the two estimates generated using literature equations based on the differential molar heat capacity assumptions.
Conclusions. For the compounds studied, Cp was not negligible and was closer to Sf than to zero. However, neither of the two assumptions was valid for accurately estimating the ideal solubility as given by the full equation. 相似文献
5.
Purpose. To characterize the surface thermodynamic properties of two polymorphic forms (I and II) of salmeterol xinafoate (SX) prepared from supercritical fluids and a commercial micronized SX (form I) sample (MSX).
Methods. Inverse gas chromatographic analysis was conducted on the SX samples at 30, 40, 50, and 60°C using the following probes at infinite dilution: nonpolar probes (NPs; alkane C5-C9 series); and polar probes (PPs; i.e., dichloromethane, chloroform, acetone, ethyl acetate, diethyl ether, and tetrahydrofuran). Surface thermodynamic parameters of adsorption and Hansen solubility parameters were calculated from the retention times of the probes.
Results. The free energies of adsorption (-GA) of the three samples obtained at various temperatures follow this order: SX-II > MSX SX-I for the NPs; and SX-II > MSX > SX-I for the PPs. For both NPs and PPs, SX-II exhibits a less negative enthalpy of adsorption (HA) and a much less negative entropy of adsorption (SA) than MSX and SX-I, suggesting that the high -GA of SX-II is contributed by a considerably reduced entropy loss. The dispersive component of surface free energy (s
D) is the highest for MSX but the lowest for SX-II at all temperatures studied, whereas the specific component of surface free energy of adsorption (-GA
SP) is higher for SX-II than for SX-I. That SX-II displays the highest -GA for the NP but the lowest s
D of all the SX samples may be explained by the additional -GA change associated with an increased mobility of the probe molecules on the less stable and more disordered SX-II surface. The acid and base parameters, KA and KD, that were derived from HA
SP reveal significant differences in the relative acid and base properties among the samples. The calculated Hansen solubility parameters (D, P, and H) indicate that the surface of SX-II is the most polar and most energetic of all the three samples in terms of specific interactions (mostly hydrogen bonding).
Conclusions. The metastable SX-II polymorph possesses a higher surface free energy, higher surface entropy, and a more polar surface than the stable SX-I polymorph. 相似文献
6.
Dalpiaz Alessandro Scatturin Angelo Pavan Barbara Varani Katia IJzerman Adriaan P. Borea Pier Andrea 《Pharmaceutical research》1999,16(7):1054-1058
Purpose. A thermodynamic analysis of the binding to rat cortex adenosine A1, receptor of N6-substituted (full agonists) and N6-substituted-deoxyribose (partial agonists) adenosine derivatives was performed. The intrinsic activity of the compounds was evaluated by measurements of the inhibition of forskolin stimulated 3, 5-cyclic adenosine mono-phosphate (c-AMP) levels in isolated epididymal rat adipocytes.
Methods. The thermodynamic parameters G° (standard free energy), H °(standard enthalpy), and S° (standard entropy) of the binding equilibrium were determined by means of affinity measurements carried out at different temperatures (0, 10, 20, 25, 30° C). Levels of c-AMP were evaluated performing competitive protein binding assays.
Results. The binding of the ligands increases with temperature enhancement and, as a consequence, is totally entropy driven. Standard entropy values correlate significantly with intrinsic activity ones.
Conclusions. It is proposed the data obtained by these in vitro experiments can be used to investigate the in vivo pharmacodynamic of A1, full and partial agonists. 相似文献
7.
Purpose. To define an index based on the van't Hoff equation that can be used as a screening tool for predicting poly(ethylene) glycol (PEG)-drug eutectic composition.
Methods. Phase diagrams of PEG with ritonavir, ibuprofen, fenofibrate, naproxen, and griseofulvin were constructed using differential scanning calorimetry, hot stage microscopy and powder X-ray diffractometry. Previously reported phase diagrams were also used to test the predictive capability of the index.
Results. This work shows that a modified van't Hoff equation can be used to model the drug liquidus line of these phase diagrams. The slope of the liquidus line depends on the melting point (Tf
d) and heat of fusion (Hf
d) of the drug and describes the initial rate at which the eutectic or monotectic point is approached. Based on this finding, a dimensionless index Ic was defined. The index can be calculated from the melting points of the pure components and heat of fusion of the drug. In addition to the compounds listed above, the index was found to predict the eutectic composition for flurbiprofen, temazepam and indomethacin. These compounds range over 150°C in Tf
d, and from 25-65kJ/mole in Hf
d.
Conclusion. Using Ic the approximate eutectic composition for eight different compounds was predicted. The index provides a useful screening tool for assessing the maximum drug loading in a drug-polymer eutectic/monotectic formulation. 相似文献
8.
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
9.
Wolfgang Löscher 《Pharmacy World & Science》1992,14(3):139-143
TheE isomer of 2-ene-valproic acid (2(E)-VPA) is the major active metabolite of the antiepileptic drug valproate (VPA) in various species, including humans. Experimental studies on 2(E)-VPA and VPA indicate that 2(E)-VPA may be a useful antiepileptic drug itself. 2(E)-VPA has the same wide spectrum of anticonvulsant activity as VPA with a somewhat higher anticonvulsant potency in rodent and dog models of different seizure types. As VPA, 2(E)-VPA increases presynaptic -aminobutyric acid (GABA) levels in the brain, presumably by an effect on GABA synthesis and/or GABA degradation. 2(E)-VPA is a much more potent inhibitor of the human brain GABA-degrading enzyme than VPA. In high doses. 2(E)-VPA is more sedative in rodents than is VPA; LD50 values are about the same. In mouse and rat models for teratogenicity, 2(E)-VPA does not induce teratogenic effects, whereas VPA is teratogenic in these models. Pilot rat studies on liver toxicity of VPA and VPA metabolites suggest that 2(E)-VPA is not hepatotoxic. In view of the rare but serious hepatotoxicity and teratogenicity of VPA in humans, 2(E)-VPA obviously merits interest as a valuable alternative drug in antiepileptic therapy. 相似文献
10.
Geinoz S Rey S Boss G Bunge AL Guy RH Carrupt PA Reist M Testa B 《Pharmaceutical research》2002,19(11):1622-1629
Purpose. The purpose of this work was to assess the molecular properties that influence solute permeation across silicone membranes and to compare the results with transport across human skin.
Methods. The permeability coefficients (log K
p) of a series of model solutes across silicone membranes were determined from the analysis of simple transport experiments using a pseudosteady-state mathematical model of the diffusion process. Subsequently, structure-permeation relationships were constructed and examined, focusing in particular on the difference between solute octanol/water and 1,2-dichloroethane/water partition coefficients (log P
oct-dce), which reported upon H-bond donor activity, and the computationally derived molecular hydrogen-bonding potential.
Results. The hydrogen-bond donor acidity and the lipophilicity of the compounds examined greatly influenced their permeation across silicone membranes. Furthermore, for a limited dataset, a significant correlation was identified between solute permeation across silicone membranes and that through human epidermis.
Conclusion. The key molecular properties that control solute permeation across silicone membranes have been identified. For the set of substituted phenols and other unrelated compounds examined here, a similar structure-permeation relationship has been derived for their transport through human epidermis, suggesting application of the results to the prediction of flux across biological barriers. 相似文献
11.
Gérard Fabre Christophe Briot Eric Marti Jean -Pierre Montseny Martine Bourrié Danielle Massé Yves Berger Jean -Paul Cano 《Pharmacy World & Science》1992,14(3):146-151
The metabolism of 2-n-propyl-2-pentenoate (2-VPA) was evaluated in human hepatic microsomal fractions. Two biotransformation pathways have been particularly investigated. In the presence of the cytochrome P-450 co-factor, NADPH, the main metabolites recovered were 3-VPA, 2,4-VPA and VPA. The glucuronidation of 2-VPA was also studied on various hepatic microsomal fractions using Brij® 35 as activator and UDP-glucuronic acid as co-factor. A large interindividual variability occurred in this metabolic pathway.K
m
andV
max were 0.85 mmol/l and 1.75 nmol·min–1·mg–1, respectively, for 2-VPA and 1.11 mmol/l and 5.71 nmol·min–1·mg–1 for VPA, respectively. The good correlationr=0.82; p<0.001) observed between the glucuronidation of VPA and 2-VPA as well as the mutual inhibition of each other's glucuronidation strongly suggests that (a) common single UDP-glucuronosyltransferase isoenzyme(s) was (were) involved in this glucuronidation step. The glucuronidation of specific substrates for various UDP-glucuronosyltransferase isoenzymes showed a good relationship between the glucuronidations of 2-VPA and morphine, a substrate for UDP-glucuronosyltransferase-2B. Moreover, morphine competitively inhibits A -VPA glucuronidation. It seems the same isoenzyme or, at least, (a) very closely related isoenzyme(s) belonging to UDP-glucuronosyltransferase-2 isoenzyme, is involved in 2-VPA glucuronidation. 相似文献
12.
No HeadingPurpose. To understand the structural requirements in designing epitope-bearing oligonucleotides with high antibody-binding affinity.Methods. Binding affinity (KA) and stoichiometry (n) of dinitrophenyl (DNP)-derivatized model 27-mer oligonucleotides (ODNs), GGG(AAA)7 GGG, to monoclonal anti-trinitrophenyl (TNP) antibodies were determined using isothermal titration calorimetry (ITC). Structural variations were made in the ODNs to assess the effects of antigenic valence, epitope density, inter-epitope linker length, and linker flexibility. Binding isotherms were fitted with a single binding-site model to obtain KAand n, from which changes in Gibbs free energy (G°), entropy (S°), and enthalpy (H°) were derived.Results. As expected, ligands displaying increased epitope density showed increases in KA: for example, KAfor (DNP)2-Cys is 3.3-fold greater than that for DNP-Lys. Introduction of multiple DNP groups via long and flexible linkers to one end of the 27-mer ODN resulted in a bivalent behavior with n value of 1. A bivalent ligand, derivatized at both ends with a long and flexible linker, failed to form an immune complex when hybridized to its antisense strand, presumably due to intercalation of the DNP moiety to the double strand. ODNs derivatized with flexible linkers exhibited a higher KAthan those with a rigid linker. Ligands with flexible inter-epitope linkers measuring distances of 110, 60, and 40 Å yielded 13-, 30-, and 13-fold increases in KA, respectively. The combination of these factors; namely, bivalence, flexible inter-epitope linkers, and optimal inter-epitope distance, resulted in an overall 66-fold increase in KA. Thermodynamic analysis of binding indicates that the formation of high-affinity ODN-IgG complexes was a spontaneous and exothermic event, characterized by large negative S°, H°, and G° values.Conclusions. All four strategies tested during this investigation, namely bivalence, epitope density, inter-epitope linker flexibility, and optimal inter-epitope distance, proved to be useful in improving the binding affinity of DNP-labeled ODNs to anti-TNP IgG. The final ODN design incorporating these strategies will be used in testing the systemic pharmacokinetic advantage gained from complexing such ODNs to IgG. 相似文献
13.
Rats were trained in a water maze to discriminate between IP injections of 3 mg/kg 9- (9(11)-THC) and its vehicle. Both 8- and 9(11) were generalized to the training drug. In contrast to our observations in rhesus monkeys, where 9-THC is at least 100 times less potent than 9-THC, 9(11) was found to be only seven times less potent in the rat. Relative potencies, expressed as the dosage at which 50% of the animals gave drug responses (ED50) were 1.8 mg/kg and 12.2 mg/kg for 9-THC and 9(11) respectively. Twenty-four hours after receiving 7×ED50=12 mg/kg 9 the tests showed intermediate results when conducted with the training dosage; 4×ED50=50 mg/kg 9-THC 48 h prior to the training dosage of 3 mg/kg 9-THC completely blocked drug-appropriate responses. Coinjection of ED50 dosages of 9- and 9(11)-THC led to 90% drug responses, demonstrating the additivity of the cannabis-like effect of both cannabinoids. Differences in the individual sensitivity of the rats to the tested cannabinoids were observed. Findings are interpreted in terms of the receptor mechanism for cannabis-like activity.This paper is dedicated to the memory of Dr. M. Binder who died on February 15, 1984 相似文献
14.
The location of amino acids in soluble or membrane proteins is related to the hydrophobicity of the side chains. Amino acid hydrophobicity values are based upon the thermodynamics of transfer from an aqueous to a nonaqueous environment. However, for certain hydrophilic residues uncertainty exists on the appropriate hydrophobicity values. We have measured the octanol- water partition coefficients (P
o/w) of tripeptides of the sequence N-14-C-acetyl-Ala-JT-Ala-NH-tButyl (AcAlaXAlaNHtButyl), where the central residue X was either Gly , Ala, Phe, Trp, Pro, His, Asp, or Glu. The P
o/w for the tripeptides agreed reasonably well with values calculated by the fragment method of D. J. Abraham and A. J. Leo (Proteins Struct. Func. Gen. 2, 130–152, 1987). The log P
o/w of the uncharged form was 1.6,2.7, and 2.5 greater than the log P
o/w of the ionized form for the His, Asp, and Glu peptide, respectively. The new data on the pH dependence of the ionizable side chains, His, Asp, and Glu, should result in better prediction of the partition coefficient of peptides as a function of pH. The thermodynamic parameters were determined from the temperature dependence of partitioning. In the temperature range studied (2 to 65°C) the transfer of tripeptides from water to octanol was entropy governed except for the ionized peptides. A heat capacity term was necessary to account for the transfer of tripeptides containing non polar residues. The heat capacity change for transfer from water into octanol was –45, –73, –81, and –88 cal/mol K for Ala, Phe, Trp, and Pro peptides, respectively. Peptides containing Gly, His (pH 7.2), and the uncharged forms of Asp, Glu, and His did not show a significant change in heat capacity. The side-chain contribution of the central residue X (G
X) to the free energy of transfer was obtained from the difference between the free energy o f transfer of the peptide containing the central residue X and the Gly peptide; G
X = G
(AcAlaGlyAlaNHtButyl) - G (AcAlaGlyAlaNHtButyl). The relative order of hydrophobicity of the side chains correlated well with previous studies. However, a significant difference was found for the absolute hydrophobicity between the present study and experimental data on N-acetyl amino acid amide derivatives (J. Fauchere and V. Pliska, Eur. J. Med. Chem. 18(4), 369–375, 1983). The G
X values at pH 7.2 were 0, –0.13, –2.19, –2.52,–0.29, –0.16, 3.50, and 3.12 kcal/mol for Gly, Ala, Phe, Trp, Pro, His, Asp, and Glu, respectively. These hydrophobicity values in a tripeptide environment provide suggested values for a hydrophobicity scale. 相似文献
15.
Comparison of CYP3A Activities in a Subclone of Caco-2 Cells (TC7) and Human Intestine 总被引:2,自引:0,他引:2
Raeissi Shamsi D. Guo Zuyu Dobson Glenn L. Artursson Per Hidalgo Ismael J. 《Pharmaceutical research》1997,14(8):1019-1025
Purpose. To compare the activity of the CYP3A enzyme expressed by TC7, a cell culture model of the intestinal epithelial cell, to the activity of human intestinal CYP3A4, using terfenadine as a substrate.
Methods. The metabolism of terfenadine was investigated in intact cells and microsomal preparations from TC7, human intestine, and liver. The effect of two CYP3A inhibitors, ketoconazole and troleandomycin (TAO), on the metabolism of terfenadine was also examined.
Results. Only hydroxy-terfenadine was detected in TC7 microsomal incubations. In contrast, azacyclonol and hydroxy-terfenadine were detected in human intestinal and hepatic microsomal incubations. The Km values for hydroxy-terfenadine formation in TC7 cells, intestine and liver microsomes were 1.91, 2.5, and 1.8, M respectively. The corresponding Vmax values were 2.11, 61.0, and 370 pmol/min/mg protein. Km values for azacyclonol in intestinal and hepatic samples were 1.44 and 0.82 M and the corresponding Vmax values were 14 and 60 pmol/min/mg protein. The formation of hydroxy-terfenadine was inhibited by ketoconazole and TAO in human intestine and TC7 cell microsomes. The Km and Vmax values for terfenadine metabolism in intact TC7 cells were similar to those from TC7 cell microsomes.
Conclusions. Our results indicate that TC7 cells are a potentially useful alternative model for studies of CYP3A mediated drug metabolism. The CYP3A expressed by TC7 cells is not CYP3A4, but probably CYP3A5, making this cell line suitable for studies of colonic drug transport and metabolism. 相似文献
16.
A. Moschovakis D. Liakopoulos A. Armaganidis V. Kapsambelis G. Papanikolaou G. Petroulakis 《Psychopharmacology》1978,58(2):181-183
Nest-building, a behavioral model shown to be disrupted by hallucinogens, has never been used to answer questions concerning the psychotomimetic effects of
9-THC. Several fractions of cannabis and tobacco pyrolysis products were tested consecutively in the same procedure. The following drugs were injected i.p. under a saline-drug-saline schedule: d-amphetamine (6 mg/kg), pentobarbital (25 mg/kg),
9-THC (10 mg/kg, 5 mg/kg, 2.5 mg/kg), the cannabis fractions designated Is (water soluble products), IIs (nonsoluble, nonvolatile products), IIIs (it comprises what is inhaled by a common hashish smoker), and analogous fractions of tobacco pyrolysis products designated IIIB (what is inhaled by a common tobacco smoker), IIB and IB.The effects of
9-THC (10 mg/kg), IIs, and IIIs were quite similar as far as the disruption of the normal behavioral pattern is concerned. d-Amphetamine,
9-THC (5 mg/kg), and IIB disrupted the normal behavioral pattern as well. The similarity of the effects of IIs and IIIs was unexpected in view of the different contents of cannabinoids in these fractions. Also unexpected was the similarity of the effects of
9-THC (10 mg/kg) and IIIs (40 mg/kg containing 7%
9-THC) as well as the activity of fraction IIIB. 相似文献
17.
Shaw Jeng-Pyng Fishback James A. Cundy Kenneth C. Lee William A. 《Pharmaceutical research》1995,12(12):1937-1942
Purpose. To determine the degradation rates and pathways of GS-522, a potent oligodeoxynucleotide (GGTTGGTGTGGTTGG) inhibitor of thrombin, in serum and plasma.
Methods. A stability-indicating, anion-exchange HPLC method was developed and used to determine concentrations of GS-522 and metabolites.
Results. In monkey plasma at 2 µM or below, the degradation of GS-522 can be fit to a first-order exponential with a kp
obs ~ 0.01 min–1. At 3 µM and above the degradation process deviates from a monoexponential decay profile. An initial fast degradation process is followed by a slower phase with an observed rate constant equal to that observed at 2 µM and below. In monkey serum, the KMand Vmaxare 8.4 µM and 0.87 µM min–1, respectively.
Conclusions. The kinetics are consistent with an equilibrium binding of GS-522 to prothrombin in plasma (Kd = 50 nM) which saturates at GS-522 concentrations >2 µM. Compared to a scrambled sequence (GGTGGTGGTTGTGGT), with no defined tertiary structure, GS-522 is 4-fold more stable in serum. The metabolic profile in plasma is consistent with a 3-exonuclease catalyzed hydrolysis of GS-522. 相似文献
18.
Girard P. Saumet J. L. Dubois F. Boissel J. P. 《European journal of clinical pharmacology》1993,44(2):177-182
Summary The concentration-effect relationships of pinacidil, a peripheral vasodilator, have been measured in 12 healthy adults who received placebo or pinacidil 25 mg daily for 1 week in a cross-over experiment. Diastolic blood pressure (DBP) and heart rate (HR) were recorded and blood samples were taken on days 1 and 7. Plasma drug concentration-time data were fitted by a biexponential function with zero-order input. The pharmacokinetic model was incorporated into a combined pharmacokinetic-dynamic model (PK-PD) using the Hill equation, which has three parameters: n, the sigmoidicity parameter, Emax the maximum effect and EC50 the concentration which gives 50% of Emax. For DBP, the parameter medians were estimated as n=5, EC50=44.6 ng · ml–1 and Emax=13.5 mm Hg.A hysteresis loop was found when HR was plotted against concentration, which could be fitted by a linear effect compartment model. Simulations showed that experimental DBP points on Day 7 could be predicted from a simulated curve computed by the model using parameters estimated on Day 1.Using the simulation, it was possible to suggest an optimal dosage regimen for pinacidil tablets. 相似文献
19.
Rats were trained in a two-lever operant box in a drug discrimination procedure to respond differentially to the effects induced by 3 mg/kg of (-)
9-tetrahydrocannabinol and the drug vehicle. Tests with (-)
8-THC and the dimethyl-heptyl (DMH) homologue of (-)
8-THC indicated that (-)
8-THC-DMH was more potent but had a slower onset of action than (-)
8-THC. Two ways of testing the onset and duration of action were compared. In one procedure (separate tests) the time course of the drug action was established by testing each time interval on separate days with a new injection each test day, whereas in the other procedure (repeated tests) all intervals were evaluated after a single injection. The results were similar for both procedures. The median time intervals for the decay of the (-)
8-THC stimulus were 122 and 127 min for the separate and repeated tests procedures respectively. The median time intervals for the onset of action of the (-)
9-THC effects of (-)
8-THC were 65 and 62 min for the separate and repeated tests procedures respectively. The median time intervals for the decay of (-)
8-THC-DMH (0.30 and 0.56 mg/kg) was between 8 and 24 h after injection. Furthermore, a stereoselective action is indicated, as (+)
8-THC (5.6 and 10 mg/kg) did not substitute for (-)
9-THC. 相似文献
20.
The purpose of the present study is to examine potentially additive effects of pentobarbital and 9-Tetrahydrocannabinol 9-THC using a drug discrimination paradigm. Three groups of pigeons were trained to discriminate between the effects induced by i.m. administrations of either (a) 0.25 mg/kg 9-THC and vehicle, (b) 4 mg/kg pentobarbital and saline, and (c) 9-THC and pentobarbital. Test probes under extinction conditions produced orderly dose generalization gradients among the drug-vs nondrug-trained animals. ED50 for pentobarbital was 1.60 mg/kg and ED50 for 9-THC was 0.10 mg/kg. Tests in birds discriminating between pentobarbital and 9-THC suggested a sharpening of the drug cue effects; tests with the vehicles resulted in approximately a random key selection (33%–66%) while tests with combinations of the two training drugs suggested that 9-THC was the more salient cue in this group. Tests with combinations of various doses of pentobarbital and 9-THC in the drug-vs nondrug-trained birds did not increase responding on the respective drug-training associated key. Thus the cue effects of pentobarbital and 9-THC were not summational under these experimental conditions. In conclusion, rather low doses of pentobarbital and 9-THC are effective as discriminative cues in pigeons and the cues thus induced are different. Combinations of the two drugs are not necessarily summational, and the pentobarbital vs the 9-THC discriminations augmented the discriminable effects of the two drugs. In addition, the analeptic drug, bemegride, antagonizes the pentobarbital (4 mg/kg) stimulus in the group trained to discriminate between this barbiturate and saline, which agrees with earlier drug antagonism data obtained among mammals (gerbils and rats), required to discriminate between barbiturates and the nondrug condition. 相似文献