Based on the fact that inclusion of a suitable binder into feed liquid and drying of a sprayed droplet in a drying chamber results in an agglomerated or encapsulated particle, salicylic acid was encapsulated or agglomerated with acacia by the spray-drying technique and dissolution rate of the encapsulated particle was examined. The rapid dissolution rate of encapsulated salicylic acid indicated that coated film of the encapsule was not hardened but rather permeable. The apparent dissolution rate constant was decomposed into the particle internal mass transfer coefficient and the diffusion layer mass transfer coefficient by the "three-film model" which represents a general dissolution process of micro-encapsule. Spray-dried encapsule prepared from slurries having a lower concentration ratio of acacia to salicylic acid than 0.2 was found to be encased with a porous film by scanning electron microscopic observation and by the dissolution rate analysis. It was found that acacia equivalent to or more than salicylic acid should be included into the feed liquid in order to obtain a well-coated spray-dried capsule and the particle internal mass transfer coefficient is linearly correlated with the reciprocal of encapsulating film thickness of non-porous encapsule.
The appearance of physical dependence of 2-(5H-benzopyrano[2, 3-b]pyridin-7-yl)-propionic acid (Y-8004) in mice and rats was compared with that of morphine as a control. Y-8004 and other compounds were given subcutaneously to test animals. In the mouse jumping test, no jumping was produced by levallorphan in mice treated repeatedly with Y-8004, while marked jumping was observed in mice treated repeatedly with morphine and then challenged with levallorphan. When repeated treatment with morphine in rats was discontinued or levallorphan was given instead of morphine, the decrease in body weight due to physical dependence was observed. In the case of Y-8004, any decrease was not exhibited under the same experimental conditions. No development of tolerance to analgesic and anti-inflammatory activity of Y-8004 was observed in mice and rats, respectively, by repeated administration. The analgesic activity of Y-8004 was not influenced by levallorphan and Y-8004 showed no influence on that of morphine. These findings suggest that Y-8004 may be a nonnarcotic analgesic differing from morphine or pentazocine.
The metabolism of carteolol hydrochloride was investigated in rats and dogs after oral administration of 14C-carteolol hydrochloride. The metabolites were identified by gas chromatography-mass spectrometry. In the rat, summation of radioactivity excreted in urine and feces during 48 hr was about 35% and 62%, respectively. The major radioactive metabolites including glucuronides were carteolol (35%) and 8-hydroxycarteolol (47%) from urine, and carteolol (35%), 8-hydroxycarteolol (20%), and dihydroxycarteolol (33%) from feces. On the other hand, in the dog, the summation of radioactivity excreted in urine and feces during 48 hr was about 62 % and 27 %, respectively. The major radioactive metabolites including glucuronides were carteolol (35%), 8-hydroxycarteolol (45%), and dihydroxycarteolol (9%) from urine, and carteolol (23%) and 8-hydroxycarteolol (61%) from feces. Carteolol and 8-hydroxycarteolol were also identified from human urine. The minor metabolites were identified as 5-hydroxy-3, 4-dihydrocarbostyril and 5, 8-dihydroxy-3, 4-dihydrocarbostyril from the rat and the dog, and as 5-carboxymethoxy-3, 4-dihydrocarbostyril from dog urine. Antagonism of 8-hydroxycarteolol, the main metabolite, against the positive chronotropic and hypotensive actions of isoproterenol was examined in anesthetized dogs.
Raw tubers of Aconitum japonicum and A. carmichaeli, which are the sources of processed aconite roots used widely as an Oriental medicine in Japan, have been assayed for the alkaloid content and composition. They have been found to contain mesaconitine or hypaconitine as the main poisonous principle and to be highly toxic. When they are processed at 120° for 40 min (to Kako-bushi), a greater part of the poisonous aconitines is hydrolyzed into the much less poisonous benzoylaconines and, together with the postulated co-occurrence of substances which reduce the toxicity of the aconitines, the tubers become essentially innocuous. It has been revealed that the processed aconite roots (Shirakawabushi), prepared by a variety of procedures (immersion into salt water, coating with lime or ash, and/or some heat treatment), show variation in the alkaloid content and composition, and still exhibit considerable toxicity. The processed aconite roots (Ho-bushi), prepared by immersion into salt water and heat treatment, have also been shown to be innoxious, since the poisonous alkaloids represented by hypaconitine have been largely converted.into benzoylaconines and further the alkaloid content has been significantly reduced. It is quite probable that, in the processed aconite roots (Ho-bushi), not only the poisonous alkaloids but also other active principles have been much decreased owing to chemical degradation by heat treatment as well as by physical loss due to extraction during processing, which is to be clarified by future pharmacological examinations. It has been shown that, when raw tubers are heated at 100° in the presence of water (conditions employed for decoction), the content of the aconitines is gradually diminished and the toxicity reduced rapidly, a fact which confirms that raw tubers become far less toxic by means of sufficient heating under these conditions.
The ground mixtures of chloramphenicol palmitate and microcrystalline cellulose were prepared using Form A (stable form) and Form B (metastable form) chloramphenicol palmitates. In spite of the difference in the original crystal structure, X ray diffraction and differential scanning calorimetry showed that almost the same micro-dispersed or "amorphous" state of the drug was obtained by the grinding. Dissolution and enzymatic hydrolysis rates of the drug in the ground mixtures were greater than that of Form A. Enzymatic hydrolysis rate of Form B was as fast as those of the ground mixture, even when its dissolution rate was not very greater than that of Form A. The four preparations, Form A, Form B, Form A ground mixture, and Form B ground mixture, were administered in a random crossover fashion to five human subjects, and drug absorption was assessed from urinary excretion data of the metabolites. After oral administration of the ground mixtures, the drug was found to be better and more uniformly absorbed. Especially, in the case of Form A, 20-fold increase in the amount of drug absorbed was observed by the grinding.
Dehydrocyclization and dehydrogenation of trimethylenediamine and aldehyde to 2-alkylpyrimidine was studied on a Pt-Rh-Al2O3 catalyst in a stream of hydrogen gas at atomospheric pressure. The reaction was carried out between 290 and 410° in a flow system. The vapor of nonaqueous solvent (benzene or alcohols corresponding to the aldehyde) and nitrogen gas were examined as a diluent instead of water vapor which was used in a previous work. By the use of benzene and alcohol as a diluent, the yield of 2-alkylpyrimidine increased markedly to 48-81% without a decay in the catalyst activity. On the other hand, the decay was observed by the use of nitrogen gas as a diluent. Reaction conditions were also examined for the formation of 2-alkylpyrimidine from trimethylenediamine with alcohol, acid, or ester ; the principal product was 2-ethylpyrimidine from 3, 3'-diaminodipropylamine induced by disproportionation of trimethylenediamine. Therefore, the desired product (2-alkylpyrimidine) could not be obtained in a good yield.
The polymorphonuclear (PMN) leucocyte suspension in the medium with or without Ca2+ was incubated with phospholipase C (PLC). In the medium without Ca2+, PLC (0.001 U/ml) caused the release of lactate dehydrogenase (LDH) and lysosomal enzymes (aryl sulfatase and β-glucuronidase) from PMN leucocytes. The release of lysosomal enzymes was significantly inhibited by dexamethasone (0.01-1 μM), prednisolone (0.01-10 μM), and hydrocortisone (0.1-100 μM), but not by indomethacin (100 μM) and phenylbutazone (100 μM). In the medium with Ca2+, PLC (1 U/ml) induced the secretion of lysosomal enzymes from PMN leucocytes without the release of LDH and loss of viability of leucocytes. This secretion of lysosomal enzymes was enhanced by the addition of 3 mM cysteine and significantly inhibited by the above anti-inflammatory drugs and colchicine in concentrations less than 10 μM. These methods may be useful as a simple test to check the effect of anti-inflammatory agents on the secretion of lysosomal enzymes.
The metabolic fate of 5-aminomethylsalicylic acid (AMS), a new analgesic agent, was examined in rabbits and rats. The blood level of AMS reached a maximum 1 hr after its subcutaneous injection in rabbits. The blood level was approximately 10% of the initial level 5 hr after the intravenous injection in rabbits, and about 90% of the given dose was excreted in urine during this period. AMS was found to be bound to plasma protein rather loosely compared to other salicylate compounds. The urinary excretion of AMS and its metabolites in rabbits was 50% in 3 hr and about 100% in 9 hr after the subcutaneous injection of AMS. The major metabolites in urine were free AMS, its glycine conjugate, and 4-hydroxyisophthalic acid, an ouidation product of AMS, which amounted to 70, 11, and 19% of the administered dose, respectively. The urinary excretion pattern in rats was similar to that in rabits.
Two new sesquiterpenoids, dihydrofuranocaulesone (I) and cauleslactone (II), were isolated from the essential oil of the subterranean part of Asarum caulescens (Aristolochiaceae). Structures of these substances were determined from chemical and spectroscopic evidences.
Several new alkalolds were isolated from Gardneria multiflora MAKINO (Loganiaceae) and structural elucidation of the six of them are presented. Alkaloids J (IX) and L (X) are trimethoxyoxindole alkaloids having a gardneramine (I) skeleton. The characteristic feature of these two alkaloids is their C-16-R configuration, which was proved by formation of the ether ring compound (XVI) on heating of IX or X in dilute hydrochloric acid. IX and X were derived from known bases, gardneramine (I) and 18-demethylgardneramine (III), respectively. Alkaloid N (XII) is also a trimethoxy oxindole alkaloid which has an α-glycol function at C-16 and C-17. This functionality was proved by the formation of an acetonide (XIX). The configurations of C-7 and C-16 in XII were determined by the generation of iminoether compound (XXI) via mesylate (XX). Gardneramine N-oxide (XIII), alkaloid M (XI), and exomethylene compound (XIV) were also isolated. Alkaloid I (V) also exists as a natural alkaloid. Alkaloidal constitution of Gardneria liukiuensis was also studied and was proved to be quite similar to that of Gardneria multiflora.
1, 3-Dipo1ar addition reaction of N-phenylmaleimide (II) with diazomethane (Ia), phenyldiazomethane (Ib), p-anisyldiazomethane (Ic), and p-tolyldiazomethane (Id) afforded the corresponding 5-phenyl-3, 3a-dihydropyrrolo[3, 4-c]pyrazole-4, 6(5H, 6aH)-dione (IIIa-d). Reaction of II with ethyl diazoacetate (If) and p-nitrophenyldiazomethane (Ig) gave, on the other hand, 5-phenyl-1, 3a-dihydropyrrolo[3, 4-c]pyrazole-4, 6(5H, 6aH)-dione (Vf, g). The addition products (IIIa-d, Vf, g) were smoothly dehydrogenated into the corresponding 5-phenylpyrrolo[3, 4-c]pyrazole-4, 6(1H, 5H)-dione (VIa-d, f, g) with bromine in acetic acid. 2-Furyldiazomethane (Ie) reacted with II to give the condensed cyclopropane derivative (IVe) and the adduct (Ve).
All neuroleptic butyrophenones examined and chlorpromazine at relatively high concentrations of 10-4 to 10-3M decreased the oxygen uptake by rat liver slices. At low concentrations of 10-5 to 10-4M, butyrophenones and chlorpromazine strongly stimulated the oxygen uptake by rat liver homogenates when glucose, pyruvate, and succinate were used as substrates, but at a high concentration of 10-3M, clofluperol, moperone, and chlorpromazine decreased the oxygen uptake, while trifluperidol and haloperidol still stimulated the oxygen uptake by liver homogenates. Clofluperol, the most potent neuroleptics among four kinds of butyrophenones used, at concentrations of 5×10-5 to 10-4M stimulated the state 4 respiration induced by succinate, β-hydroxybutyrate, and glutamate, and inhibited the oxidative phosphorylation in rat liver mitochondria. It also activated latent ATPase of liver mitochondria as same as the typical uncoupler such as 2, 4-dinitrophenol. On the other hand, at a higher concent ration above 2.5×10-4M, it caused aggregation of mitochondria and impaired the function of mitochondria. These findings suggest that neuroleptic butyrophenones may also interact with biological membranes in a similar manner as phenothiazines.
2, 6-Disubstituted oxaolo[3, 2-b]pyridazinium perchlorates (VI) were synthesized by acid-cyclization of 2-(α-oxoalkyl)-3(2H)-pyridazinones (V), derived from 6-substituted 3(2H)-pyridazinones (IV) and α-haloketones. Treatment of the quarternary salt (VIa : R1=C6H5, R2=H, R3=Cl) with KOH and NaSH gave Va and 2-phenacyl-3(2H)-pyridazinethione (VIIa), respectively. The reaction of VI with the sodium salts of ethyl cyanoacetate, malononitrile, and ethyl malonate furnished pyrrolo[1, 2-b]pyridazines (IX, XIII, and XIV). This reaction seems to be initiated by the nucleophilic addition of the reagents on C-8a position of VI, followed by ring-opening and re-aromatization to afford pyrrolopyridazine systems.
Studies were made on the oxidation of oxyhemoglobin (HbO2) by the presence of phenothiazine system tranquilizers. Methemoglobin (MHb) was formed when a salt of ethopropazine (I), promethazine (II), promazine (III), or perazine (VI) was incubated with a suspension of human erythrocytes or with HbO2 solution obtained through hemolysis of this suspension. In either of the experiments with erythrocytes and HbO2 solution, the MHb-forming effect of the compound decreased in the order of I, II, III, and VI. The HbO2-oxidizing activity of these derivatives was enhanced when they were photoirradiated before mixing of the derivatives with HbO2 solution. Chlorpromazine, methoxypromazine, thioperazine, fluphenazine, trimeprazine, and methotrimeprazine formed MHb when their acid solutions were photoirradiated before their incubation with HbO2 solution. The HbO2-oxidizing activity of phenothiazine derivatives was also enhanced when they were subjected to potentiostatic electrolysis or pyrolysis. The amount of MHb formed in the incubation mixture paralleled the amount of semiquinone free radicals produced from the derivatives. On the basis of the results of comparative examinations on the HbO2-oxidizing activity, spectral change in the ultraviolet and visible regions, and polarographic half-wave potentials of the derivatives, it was presumed that, in the case where untreated phenothiazine derivatives were involved, cation radicals produced by some oxidizing substance in the incubation mixture played an important role in the formation of MHb from HbO2.
Pharmacological effect of 28 kinds of nucleosides and nucleotides was tested from the point of their effect in prolonging the sleeping time induced by various hypnotics in dd-I strain male mice. It was observed that adenosine, adenosine 2'- and 3'-monophosphate had several advantages of prolonging the sleeping time, compared with other test compounds.
Optimum conditions for the determination of chloroquine in biological materials using gas chromatograph equipped with 10 mCi 63Ni electron capture detector has been investigated. A U-shaped glass column (3 mm × 2 m) was packed with 3% silicone OV-17 coated Gaschrom Q (mesh 100/120). Nitrogen was used as a carrier gas. The column oven was regulated to 260°, and the detector oven and the injection port were at 280°. Chloroquine was extracted with hexane from the standard solution or rabbit urine saturated with potassium carbonate. The calibration curve was drawn with the use of O-ethyl O-(p-nitrophenyl) phenylphosphonothioate as an internal standard. A few nanogram chloroquine can be determined by this procedure.
AC and DC polarographic studies were carried out on 2', 3'-isopropylideneadenosine. DC polarography showed the presence of a linear relation between the limiting current of the dropping mercury electrode and its mercury pressure. It also showed that the polarographic reduction of 2', 3'-isopropylideneadenosine was governed by the diffusion rate.
Twenty-three compounds were isolated from the calyx of Diospyros kaki THUNB. (Ebenaceae). Stearic acid, palmitic acid, succinic acid, syringic acid, vanillic acid, gallic acid, kaempferol, quercetin, trifolin, hyperin, β-sitosterol, β-sitosteryl-β-D-glucoside, friedelin, oleanolic acid, ursolic acid, and 19α-hydroxyursolic acid were identified with the respective authentic samples.
A rapid estimation procedure utilizing high-speed liquid chromatography is described for the determination of acrinol (6, 9-diamino-2-ethoxyacridine lactate monohydrate) in pharmaceutical preparations. Separation can be achieved within 7 min at 45° (flow rate, 2.1 ml/min) employing a 1 m×2.1 mm id. column packed with Zipax SAX using 0.05M NaClO4 (pH 3.3) solution as an eluant in a Du Pont 830 liquid chromatograph. Acrinol in a pharmaceutical preparation was extracted with 20% (v/v) AcOH and injected into a column. Accuracy in this method was found to be less than ±1.5% with the relation Y=0.251x+0.912 (X=quantity of acrinol in ng, Y=peak height of acrinol in mm) and a relative coefficient of 0.999.