Some Glycyrrhiza species grown in several domestic research gardens of medicinal plants were collected by the Osaka University of Pharmaceutical Sciences and were cultivated to compare their morphological properties. HPLC profile analysis was performed and index compounds of MeOH extracts of aerial parts and EtOAc extracts of subterranean parts were determined. Glycyrrhizin contents and growth rates of the underground parts of some types of Glycyrrhiza uralensis and Glycyrrhiza glabra were compared and four excellent types were selected as candidates for cultivation. One of them was due to Kanzo-Yashiki (Enzan, Yamanashi prefecture), where G. uralensis was cultivated in the Edo period. Alkaloidal constituents of G. uralensis and G. glabra were also investigated and anabasine (an insecticide) and a new tricyclic alkaloid were obtained.
The effects of vanadate on lipoprotein lipase (LPL), a lipid-metabolizing enzyme, were tested using isolated rat fat pads. Vanadate increased the cellular LPL content through the stimulation of intracellular transport of the enzyme for activation, probably glycosylation. The stimulated release of LPL from the fat pads by vanadate was due to the increase in intracellular Ca2+ concentration, leading to the fusion of plasma membrane with vehicle included active LPL. Although vanadate shows insulin- and heparin-mimicking effects, it appears to differ from both insulin and heparin with regard to the mechanism of action. In isolated mouse fat pads, vanadate decreased the cellular leptin content and secretion by the increased degradation via a cAMP/PKA-dependent process involving proteasome activation and/or ubiquitination. This was the reverse of the action of insulin. In hepatocytes, cAMP phosphodiesterase type 3 activity was stimulated via the increased mitogen-activated protein kinase activity by vanadate. On the other hand, the stimulation by insulin was dependent on Akt kinase activation. The effects of vanadate were additive to those of insulin, suggesting that vanadate differs from insulin with regard to the receptor-signaling cascade. Furthermore, vanadate showed antiplatelet and antithrombin activity, leading to the prolongation of blood clotting time.
Nonspecific renal radioactivity localization constitutes a problem in targeted imaging and therapy with radiolabeled antibody fragments. Based on the idea that the renal radioactivity levels should be reduced if radiolabeled compounds excreted in the urine are released from antibody fragments by tubular brush border enzymes, 3′-iodohippuryl Nε-maleoyl-L-lysine (HML) was designed as a radioiodination reagent for antibody fragments; the glycyl-lysine sequence in HML is a substrate for a brush border enzyme and m-iodohippuric acid is released by cleavage of the linkage. In normal mice, HML-conjugated Fab demonstrated low renal radioactivity levels from early postinjection times. Directly radioiodinated Fab showed migration of radioactivity from the membrane to the lysosomal fraction of the renal cells from 10 to 30min postinjection. On the other hand, the majority of the radioactivity was detected only in the membrane fraction after injection of HML-conjugated Fab. In tumor-bearing mice, HML-conjugated Fab showed a marked decrease in renal radioactivity localization without impairing the tumor accumulation. These findings indicate that HML is a useful reagent for reducing the renal radioactivity levels of antibody fragments.
Samarium(II) iodide has been employed to promote the vinylogous pinacol coupling reaction of aldehyde to α, β-unsaturated ketones. The diastereoselectivity of 6-endo-trig mode products was changed by the addition of a proton source and/or HMPA and by the reaction temperature. The stereochemistry of the hydrindanone was controlled by the coordinated samarium species, resulting in the cis-orientation in respect of the hydroxyl group at C-4 and the juncture proton at C-3a under mild reaction conditions. Coronafacic acid has been synthesized from a hydrindanone prepared by the cyclization reaction of the enone-aldehyde with samarium(II) iodide.
Many patients find it difficult to swallow powdery preparations like granules and because of this do not take their medication as prescribed. The difficulty is experienced in particular with dysphagic and geriatric patients, in addition to pediatric patients, especially those who find it difficult to deal with the bitter taste of medicine. It is possible that such problems result in a high incidence of noncompliance and ineffective therapy. In contrast, it is generally known that gelatinous foods like jelly are a favorite with the elderly and infants because their rheological properties make them easy to swallow. We have developed a deglutition aid jelly that can change almost all solid preparations into gelatinous dosage form preparations, which poses no risk of aspiration or spilling from the mouth, and thus is safe. To evaluate the pharmaceutical utility of this jelly, sensory tests and videofluoroscopic assessments were performed in 10 healthy adult volunteers (20—60 years of age). During the sensory tests, this jelly showed significant improvement in diffusion of the powdery preparation in the mouth and of adhesion to the oropharynx and prolonged the time until the bitter taste of the medicine was perceived. During the videofluoroscopic assessments, there were significant changes in the total oropharyngeal transit time (mean −13.04s) and oral transit time (mean −10.69s) in the group that received the jelly, suggesting improvement in the initiation of pharyngeal contractions and reduction in the time required for the bolus to transverse the pharynx. In addition, significant improvement in the oral onset of swallowing and a significant reduction in pharyngeal swallowing delay and in the frequency of aspiration were observed in some hospitalized patients with dysphagia. This jelly could therefore contribute to improved compliance in patients who feel burdened by taking oral medications.
Photoaffinity labeling is a useful and reliable method for 1) the identification of the ligand-target receptor and 2) the structural investigation of its binding site. Using photoaffinity labeling techniques, the binding sites of four typical calcium antagonists, 1,4-dihydropyridines, benzothiazepines, phenylalkylamines, and benzothiazines, were successfully identified within the primary structure of the skeletal muscle calcium channels. The results confirm pharmacological observations of the four antagonists, which had been proposed to interact allosterically with each other. Secondarily we demonstrated that human glutathione S-transferase class π (GSTπ) is specifically photolabeled by the antidiabetic agent sulfonylurea glibenclamide (GB) and it also inhibits the enzyme activities of glutathione conjugation by GB in a competitive manner for glutathione. These results indicate that GSTπ is another target molecule of sulfonylurea since a subunit of ATP-sensitive potassium channels is well known to be a sulfonylurea receptor. This review focuses on photoaffinity labeling techniques as a useful tool for drug discovery and development.
Development of drug delivery systems to achieve site-specific delivery or prolonged retention in the circulation has attracted attention, because new types of drugs are expected to be created with advances in life science and biotechnology such as the Human Genome Project. We have tried to develop a new administration route for drug targeting to the liver, since drug administration by the intravenous and oral routes makes it difficult to achieve a local site of action in the liver. Although direct application to the liver surface should result in local drug distribution, drug absorption from the liver surface has not been reported in the literature. Therefore we analyzed the absorption mechanism of several organic anions and dextrans with different molecular weights as model drugs, after application to the rat liver surface in vivo, employing a cylindrical diffusion cell. Every compound appeared gradually in the plasma, followed by excretion into the bile and/or urine, indicating the possibility of drug absorption from the liver surface. A specific transport system might not be involved in the absorption process from the liver surface, because the effect of dose and transport inhibitors on the absorption was not recognized. In addition, molecular weight was found to be a determining factor in absorption from the liver surface. The targeting efficacy was considerably enhanced by application to the liver surface, as compared with intravenous administration. Moreover, we have identified important physicochemical and pharmaceutical factors determining the absorption rate of a drug from the liver surface for clinical use. Consequently, drug application to the liver surface could improve availability in the desired site of a new drug such as bioactive compounds and genomic medicines, by combination with appropriate chemical and pharmaceutical formulation modifications.
A highly selective and sensitive method based on a novel concept is introduced for the assay of biological substances. This method is based on an intramolecular excimer-forming fluorescence derivatization with a pyrene reagent, followed by reverse-phase HPLC. Polyamines, polyphenols, and dicarboxylic acids, which have two or more reactive functional groups in a molecule, were converted to the corresponding polypyrene-labeled derivatives by reaction with the appropriate pyrene reagent. The derivatives exhibited intramolecular excimer fluorescence (440—520nm), which can clearly be discriminated from the monomer (normal) fluorescence (360—420nm) emitted by pyrene reagents and monopyrene-labeled derivatives of monofunctional compounds. With excimer fluorescence detection, highly selective and sensitive determination of polyamines, polyphenols, and dicarboxylic acids can be achieved. Furthermore, the methods were successfully applied to the determination of various biological and environmental substances in real samples, which require only a small amount of sample and simple pretreatment.
Today pharmacists provide indispensable drug information to patients, however, few studies have examined the kind of information that patients want, or their satisfaction with pharmacists' advice. Therefore, we have examined a variety of factors, including individual patient characteristics, in order to identify ways to provide useful and appropriate drug information on an individual basis. In short, the aim of this study was to develop a drug information service that addresses patient needs. A prospective survey of patient satisfaction with the level of care provided by pharmacists,before and after a telephone counseling session, was performed over a 9 month period (2000—2001). Along with satisfac-tion ratings, the content of the interviews was assessed, along with patient characteristics. Correspondence analysis was used to classify the content of the consultations, and cluster analysis was performed to classify caller characteristics. In total, 2022 people were counseled. It should be noted that, on occasion, family members were interviewed instead of the patients themselves. The average counseling session was 11.5 minutes (n=1876). Patients expressing the least dissatisfaction prior to counseling tended to have the highest satisfaction levels after counseling. Almost all patients were satisfied with the counseling they received. An association was found between levels of pre-counseling dissatisfaction and time spent counseling patients over the telephone. No dimensions of high inertia were identified by correspondence analysis of consultation content and patient characteristics (n=1667), however, questions regarding “efficacy and indications”, “dosages and administration”, “anxiety of adverse events”, “realization of adverse events”, and “interactions” were deemed similar by correspondence analysis. This study shows that patient perceptions regarding drug information services differ from those of pharmacists. Furthermore, several subtypes of patients were identified, based on their responsiveness to counseling. Pharmacists should take this into consideration when standing face-to-face with patients in the setting of their pharmacy practice.
This study was performed to establish a convenient mouse model for the evaluation of nickel allergy. For sensitization, 0.2g of nickel sulfate in petrolatum was applied 4 times every other day to the shaved dorsal skin. Seven days after the first application of the nickel sulfate salt sample, the antigen-specific metal allergy reaction was estimated based on the swelling response of the footpad injected with 20 μl of nickel sulfate salt in saline. Percutaneously applied nickel powder in petrolatum, as well as the original nickel salt sample, induced a significant nickel allergy reaction. Therefore, it is suggested that this system is applicable for the evaluation of antimetal allergic substances.