In order to investigate supersensitization induced by guanethidine, the effect of guanethidine on the dose-response curves to norepinephrine and other agonists (acetylcholine and histamine) was examined using the vas deferens of guinea pigs. The degree of supersensitivity to norepinephrine was dose-dependent (3×10-5M to 1×10-6M guanethidine) and the maximum degree was almost the same as that induced by cocaine. Guanethidine did not increase the maximum response to norepinephrine. In the presence of a low concentration of cocaine, guanethidine induced a further potentiation of the response to norepinephrine ; the maximum potentiation induced by the added guanethidine was almost the same as that induced by a high concentration of cocaine or guanethidine alone. In the presence of high cocaine concentration which produced nearly maximal potentiation, addition of guanethidine did not induce further potentiation. The concentration of guanethidine required to block the sympathetic nerve was lower than that required to potentiate norepinephrine. 3×10-5M and 1×10-4M guanethidine increased the response to acetylcholine and histamine. Supersensitivity to acetylcholine produced by guanethidine was dose-dependent and guanethidine (1×10-4M) induced a slight increase in the maximum response to histamine. These results suggest that guanethidine induces supersensitization to norepinephrine to the same degree as cocaine, and induces a so-called "non-specific supersensitization"to acetylcholine and histamine.
Encapsulation of petroleum pitch charcoal of a spherical granule type was performed by the spray of dilute pyroxylin solution in ethanol, in order to use the charcoal as an adsorbent for an artificial kidney by direct hemoperfusion. The pyroxylin membrane coated on the charcoal by this method was better than that formed by other methods, coacervation and/or dipping method, in terms of physicochemical properties such as homogeneity and permeability. The adsorption rate and capacity of the charcoal were slightly decreased by the membrane coating at the ratio of 3.75-5.0 mg/g charcoal, and were five or more times higher than those of the pyroxylin-coated coconut charcoal reported by Chang. The number of free particles released from the coated charcoal by vibration at 120 rpm for 1 hr was only 100-200 per ml, which is less than the number prescribed for blood expanders by the British Pharmacopoeia. Furthermore, the residual organic solvent in the charcoal could be significantly reduced to the order of 1×102 ppm from 1-2×104 ppm by using ethanol instead of ether or dioxane as a solvent for pyroxilin.
The essential oil of the radix of Anthriscus sylvestris HOFFM. was examined. α-Pinene, β-myrcene, d-limonene, p-cymeme, p-cymenene, γ-terpinene, terpinolene, l-α-fenchyl alcohol, l-α-fenchyl acetate, benzaldehyde, and sesquiterpenes were identified from the neutral part. 3-Methoxy-4, 5-methylenedioxycinnamyl alcohol (anthriscinol), (Z)-2-angeloyloxy-methyl-2-butenoic acid and desoxypodophyllotoxin were isolated from the residue of steam distillation of the etherial extract. Stigmasterol, β-sitosterol, campesterol, stigmasteryl D-glucoside, fatty acids, glycerides, esters and normal alcohols were isolated from the methanolic extract.
Two new furanoeremophilenolides, farformolide A (IV) and farformolide B (V) in addition to three known terpenes (bakkenolide A (I), α-amyrin (II) and brein (III)) were isolated from the herbs of Farfugium japonicum (L. f.) KITAMURA var. formosanum (HAY.) KITAMURA (Ligularia tussilaginea BURM. var. formosana HAYATA) (Compositae) were isolated. Spectral investigation shows that these new sesquiterpenes, farformolide A and B should have the stereostructures of 3β-angeloyloxy-10β-hydroxyermophilenolide (IV) and 6β, 8β-dimethoxy-10β-hydroxyeremophilenolide (V), respectively.
Relationship between chemical structure and pharmacological activity was examined in ω-amino (substituted) acetamidodiphenyl derivatives. Samples were synthesized by the application of p-chloronitrobenzene or 1, 4-dichloro-2'-nitrobenzene to the potassium salt of the corresponding phenols to form 4 (or 2)-nitrodiphenyl ethers, which were reduced with stannous chloride and conc. hydrochloric acid, and the products acylated to ω-chloroacetamidodiphenyl ethers. The objective compounds (49 samples) were then obtained by the application of corresponding aliphatic secondary amines. Anti-acetylcholine and antihistamine activities of these samples were examined by the Magnus method, using excised intestine of a guinea pig. All the compounds were found to have a papaverine-like action, which was stronger when the ω-aminoacetamide group was in the position para to the oxygen bridge, and was also elevated when the substitutent in the benzene ring was in the ortho position rather than in the meta or para position. As for the ω-amino group, compounds possessing a substituent in the piperidine ring system had a stronger activity. Therefore, 4'-chloro-4-(piperidinoacetamido) diphenyl ether (52) was selected from such compounds and its specificity to smooth muscle organs was examined in detail. By the use of excised intestinal smooth muscle, suppressive effect of 52 against contraction by barium chloride and 5-HT was 3.8 and 4.9 times, respectively, of that of papaverine. With the excised tracheal smooth muscle, 52 suppressed the contraction by acetylcholine, histamine, and barium chloride only to 60% in a high concentration. Organ specificity of 52 was seen in smooth muscle of the digestive organ system (intestinal and Oddi sphincter muscle) rather than against tracheal smooth muscle.
As one of studies on isolation of naturally occurring biologically active principles, antifungal constituents in Betula cortex were examined. Nine active principles (I-IX) were isolated by a suitable combination of column chromatography over alumina or silica gel. I-IX except V were found to be identical with paeonol (I), antiarolaldehyde (II), vanillin (III), syringaldehyde (IV), 2-hydroxy-5-(3-hydroxybutyl) benzaldehyde (VI), methyl syringate (VII), methyl vanillate (VIII), and 2, 6-dimethoxy-p-benzoquinone (IX), respectively.
An improved technique of destroying dopaminergic nerve terminals following microinjection of 6-hydroxydopamine into the unilateral striatum of mice is described. Apomorphine HCl 1.25 mg/kg produced intense rotation contralateral to the side of the lesion 10-20 days after 6-hydroxydopamine treatment. In these mice, L-dopa 20 and 40 mg/kg alone elicited marked contralateral rotation. Ergometrine maleate 10 and 20 mg/kg produced contralateral rotation which lasted over 2 hr. Methamphetamine HCl 2.5 and 5 mg/kg elicited long-lasting rotation ipsilateral to the side of the lesion. Rotation induced by apomorphine and methamphetamine was inhibited by the pretreatment with antipsychotic drugs (haloperidol, pimozide, chlorpromazine and sulpiride). Caffeine 25 and 50 mg/kg produced long-lasting contralateral rotation, which was suppressed by pretreatment with pimozide. The rotational behaviour of mice examined in the present study may be useful in the evaluation of dopaminergic stimulating activity of drugs.
N-(2-Piperazinoethyl) propionanilides were synthesized by the reduction of piperazino-acetanilide or the condensation of N-(β-bromoethyl) aniline hydrobromide and piperazines. Comparing the two methods, the condensation method is superior from the point of yield and easiness. The analgesic activity test showed that (A) N-[1-methyl-2-(4-methylpiperazino) ethyl] propionanilide (7a) possessed ca. 1/9 of the analgesic effect of morphine, and N-[2-(4-phenethylpiperazino) ethyl] propionanilide (7e) and N-[2-(3-methyl-4-phenethylpiperazino) ethyl] propionanilide (7i) possessed ca. 1/2 of the analgesic effect of pentazocine ; (B) the compound (7a), (7e), (7i) showed strong acute toxicities ; (C) methyl group at the 3-position of piperazine ring decreased analgesic activity ; (D) phenyl group at the 3-position of piperazine ring deactivated the analgesics.
The interaction of three thermotropic liquid crystal substances (I), cholesteryl myristate, cholesteryl palmitate, or cholesteryl oleate, and various alkanes or alcohols (II) was studied by gas-liquid chromatography at various temperatures, its stationary phase being composed of 10% (w/w) of I on Chromosorb W. The logarithm of specific retention volume of II vs. reciprocal of temperature was found linear within each region of smectic, cholesteric, and isotropic liquid phases of I. From specific retention volume at various temperatures, the standard free energy, enthalpy, and entropy of the solution of II in I, Δsoln GΘ2, Δsoln HΘ2, and Δsoln SΘ2, were calculated. Δsoln GΘ2 lowered by ca. 2.5 kJ mol-1 as II molecules became longer by one methylene group. The addition of hydroxyl group to II resulted in the lowering of Δsoln GΘ2 by ca. 10 kJ mol-1. Higher values of Δsoln HΘ2 and Δsoln SΘ2 were obtained in liquid crystals than in isotropic liquid phase of I, showing an extensive destruction of liquid crystal structure of I. The difference of Δsoln HΘ2 and Δsoln SΘ2 between liquid crystal and isotropic liquid phase increased as molecules of II became longer. It was concluded that the greater solubility of longer molecules of II, as shown in lower Δsoln GΘ2, was mainly due to the contribution of Δsoln SΘ2.
1, 3-Bis (hydroxymethyl)-(IIb, IVf, IVg), 1-hydroxymethyl-(IIe), 3-hydroxymethyl-β-carboline (IIc, IVe) derivatives, hydroxymethyl-oxo-yohimban (Vb) and hydroxymethyl-indolo-quinolizidine (IXb), -indolizidine (Xb) were synthesized their pharmacological activity examined. 2-Benzyl-1, 3-bis (hydroxymethyl)-1, 2, 3, 4-tetrahydro-β-carboline (IIb) hydrochloride was found to have anti-inflammatory activity with an effect almost equal to that of oxyphenbutazone.
The effect of extracts from 6 varieties of Kanpo-prescriptions (Saiko-Keishi-Kankyo-Toh, Shakuyaku-Kanzoh-Toh, Shoseiryu-Toh, Sho-Saiko-Toh, and Otsuji-Toh) on rat serum constituents at 6 hr after intraperitoneal administration was examined. Estimation of serum constituent concentrations were carried out with an automatic method. Administration of the extracts resulted in decrease of blood urea nitrogen (BUN) and increase of total cholesterol (T. Chol.) concentration in rat serum. In rats treated with Saiko-Keishi-Kankyo-Toh, BUN was maximally decreased at 6-8 hr (30%) and T. Chol. was maximally increased at 8-12 hr (21%). In Shakuyaku-Kanzoh-Toh administration, BUN was maximally decreased at 4-8 hr (46%) and T. Chol. was maximally increased at 6-12 hr (33%). In Sanoh-Shashin-Toh administration, BUN was maximally decreased at 6-8 hr (45%) and T. Chol. was maximally increased at 8-12 hr (39%). Concentrations of glucose, tri-glyceride and uric acid were not different from the control values. Furthermore, the most effective dose for each crude extract from 3 varieties of Kanpo-prescriptions was 10-20 mg/rat.
The polymeric forms of silicic acid in sodium aluminosilicate gel were studied by the trimethylsilylation method. Anions such as SiO44-, Si2O76-, Si3O108-, Si4O128-, Si6O1710-, soluble polysilicic acids expressed as Si2nO5n+22 (n+2)-, and insoluble steric network polysilicic acids were found to be present in the gel. The composition of these polysilicic acids was remarkably affected by the kind and concentration of sodium silicate, reaction temperature, and SiO2/Al2O3 ratio. Further, the gel structure of sodium aluminosilicate varies with calcination temperature. Condensation among soluble polysilicic acids occurs at 200-400°, and the growth of siloxane bond with destruction of metallsiloxane bond occurs at the temperature range over 400°.
The influence of protein binding displacement on sulfonamide blood levels was studied, using salicylic acid as the displacing drug. When five different sulfonamides were orally administered with salicylic acid to rabbits, blood levels of sulfadimethoxine and sulfisoxazole which shown high binding to bovine serum albumin (BSA) markedly decreased, whereas blood levels of sulfanilamide which shows low binding to BSA did not change. In addition, a significant correlation (r=-0.974) was observed between the decrease in sulfonamide blood levels and the increase in unbound sulfonamide concentrations. These results indicate that protein binding displacement is an important determinant affecting the blood levels of highly bound drugs.