Organisms utilize the only D-enantiomer of ribose as a sugar unit of nucleic acids. This homochirality of nucleic acids is considered to be essential for their higher-order structures and functions. Although there had been a few reports on the synthesis of L-deoxynucleosides, effects of the substitution of L-ribose for the D-enantiomer on the structure and properties of nucleic acids have hardly been investigated due to difficulties in large-scale synthesis of L-deoxynucleosides. We have developed an approach for the efficient, short step synthesis of L-deoxynucleosides, and have investigated the structure and properties of oligonu-cleotides containing them. The double-helical conformations of an L-hexadeoxynucleotide, L-d(CGCGCG) were clearly shown to be an exact mirror image of those of the corresponding natural one by CD (circular dichroism) and X-ray crystallographic analysis. This L-hexadeoxynucleotide was applied to the study of the specific double-stranded DNA recognition mechanism of bleomycin. It was found that the conventional DNA-binding domain of bleomycin binds to the L-hexadeoxynucleotide to essentially the same extent as natural one, although bleomycin can not cleave it. This result suggests that the DNA-binding domain is not responsible for the specific DNA recognition. Thus, L-DNA would be useful for distinguishing between enantio-specific and nonspecific interactions in DNA-drug interaction studies. The structures of heterochiral oligonucleotides, which contain an unnatural L-nucleotide residue in the sequence of natural type of DNA chains, were investigated by UV and 1H-NMR experiments. The results demonstrated that the L-nucleotide residue in the heterochiral oligonucleotide forms stable Watson-Crick base-pairing with the complementary natural residue, while the overall duplex stability is slightly decreased. The unusual conformational features of the L-nucleotide residue in the heterochiral DNA may be useful for the design of a novel antisense molecule resistant to nucleases in vivo.
We developed pharmaceutical management and guidance services for inpatients in a ward of circulatory medicine, considering clinical and economical standpoints. In these services, pharmacists deliver drugs prescribed for inpatients with individual drug information papers, explain to them about their drugs using information papers and give counsel. Since most of the patients were aged people, developing many kinds of diseases and taking many kinds of drugs, they had many problems such as lack of knowledge of the effects of drugs. First, we surveyed views of patients, physicians and nurses on these services. Consequently, all of them advised us that "pharmacists should explain to patients about the prescribed drugs using information papers." The patients preferred pharmacists as expositors of drugs to physicians or nurses. The physicians considered that "pharmacists have to attach importance to clinical information and package-inserts of drugs and explain to patients about drug information using pamphlet in response to the understanding of patients." The nurses wanted to cooperate with pharmacists in "improving medication compliance." On the basis of these views, we improved our services. Next, we made a survey of patients'knowledge about their drugs. We found that in the patients the level of knowledge concerning "ways, " "effects" and "reasons" of taking drugs and that of "compliance" and "satisfaction in taking drugs" were improved through these services. The patients reentered in the hospital kept a high level. The ratio of patients taking drugs by themselves increased. Last, we also applied this method to wards of "blood and collagen diseases" and "pediatrics." The demand for these services increased smoothly. We compared these services based on our method with all other services by hospital pharmacists from the viewpoint of economy. We found that only our service method was beneficial.
Effects of Reiousan, a crude drug preparation consisting of bezoar and ginseng, on blood rheology were studied. Reiousan improved the deformability of rat erythrocytes exposed to hyperosmorality and treated with phenylhydrazine. The ATP depletion in erythrocytes, the polybrene-induced erythrocyte aggregation and the oxidation of low density lipoprotein were suppressed by Reiousan. Oral administration of Reiousan also improved the erythrocyte deformability in phenylhydrazine-treated rats and delayed the thromboembolic death induced by arachidonic acid in mice. These results suggest that Reiousan has an ameliorative effect on blood rheology related to "Oketsu" syndrome in Kampo diagnostics.
For appropriate drug therapy in inpatients, not only conventional explanation of drugs, but also various measures that facilitate correct recognition of drugs by inpatients are important. Clinical pharmacists in each ward directly provide data on oral drugs. However, inpatients are provided with little data on injectable drugs, which is the other major form of drug therapy. At our hospital, we developed a system for providing injectable drug data linked to an injection order system, and began to use this system on December 1, 1998. An information sheet provided to inpatients by this system contains conventional explanation of the drug efficacy, initial symptoms of severe side effects, administration method, cautions required at the time of administration, and color photos of the preparations. A questionnaire of this system showed that both patients and physicians are generally satisfied with the information sheet. However, the opinions of physicians were divided concerning provision of all data on injectable drugs, which remains to be solved as a future problem.
Most often dry powder for inhalation are formulated as ordered mixtures of a carrier excipient and a micronized drug substance. In the present study, model powder blends were prepared from a mixture of lactose α-monohydrate, microcrystalline cellulose pellets or synthesized sugar as carrier particles, and micronized salbutamol sulfate (SS). These ordered mixtures were aerosolized by the multidose JAGO dry powder inhaler (DPI) and their in vitro deposition properties were evaluated by a twin impinger (TI). The separation force between SS particles and carrier particles was investigated by the centrifuge method. In addition, the use of the air jet sieve (AJS) method was investigated to assess the separation behavior of drug particles from carrier excipient. Powder blends were sieved through a 325 mesh wire screen of an air jet sieve at an air pressure of 1500 Pa. The amount of drug deposited at the carrier surface was analysed before and after the sieving to calculate the percentage of the drug retained. A relationship was found between in vitro deposition properties (fine particle fraction, FPF) and the separation characteristics obtained by the centrifuge method and by the AJS method. The AJS method might be a suitable alternative for evaluating separation of a drug particle from carrier particles and hence can be used for the formulation screening of the dry powder inhalation.
The spectral karyotyping (SKY) method is a novel molecular cytogenetic technique which simultaneously discerns entire chromosomes. In order to elucidate the origins of micronuclei induced under hyperthermic conditions in human lymphocyte culture, peripheral blood cells were cultured at 40°C or 42°C for 3-24 h, using the cytokinesis-block method with cytochalasin B. The induced micronuclei were identified by the fluorescence in situ hybridization (FISH) and SKY methods. At 42°C for more than 6 h, the frequency of occurrence of micronuclei in binucleated cells rose with increasing incubation time. By the FISH method, 83.3% of micronuclei induced in 24 h culture at 42°C were shown to be positive for the human centromeric probes. By the SKY method, each micronucleus induced under the hyperthermic conditions was identified unequivocally and shown to contain a specific chromosome. These results suggest that the micronuclei induced under the hyperthermic conditions in human lymphocyte culture contain chromosomes which do not migrate to the poles at the anaphase of the cell cycle because of the breakdown of the spindle apparatus.
Generic drugs are widely used with the object of cost saving in many Japanese therapeutic scenes now. The products containing the same active ingredient(s), even if they are innovative drugs or generic ones, must be designed to possess the equivalent quality. In this report, we observed the dissolution behavior patterns of three generic drugs that contain Tegafur and Uracil, drugs A, B and C, and compared them with that of an innovative product, UFT. Drugs B and C were similar to UFT in the dissolution rate of Tegafur, but drug A was not. On the dissolution rate of Uracil, all the generic products, drugs A, B and C, did not amount to the level equivalent to that of UFT. Therefore, these generic products did not indicate the same dissolution behavior pattern as UFT. It was suggested that the pharmaceutical technology used in the manufacture was not equivalent even if the products of the same dosage form contain the same kind and content of the active ingredient(s).
Dichloromethane containing metalloporphyrins [meso-tetraphenylporphyrinatomanganese(III) chloride (1) or meso-tetraphenylporphyrinatoiron(III) chloride (2)] and Bu4NClO4 was treated with an aqueous solution of NaOH (5%), and subjected to controlled potential electrolysis at -1.0 V (vs. S.C.E. (saturated calomel electrode)) in a divided cell after addition of diphenyl sulfide (3). Diphenyl sulfoxide (4) and diphenyl sulfone (5) were found in an electrolyzed solution as the reaction products. Results obtained from cyclic voltammetry and visible spectrometry suggested that the treatment of dichloromethane containing metalloporphyrins with the aqueous solution of NaOH did not change the fifth ligand of metalloporphyrins from Cl to OH. On the electrode, dissolved dioxygen was reduced to hydrogen peroxide. Compounds 1 and 2 catalyze the oxidation of 3 by hydrogen peroxide without imidazole. Compound 2 showed higher selectivity than compound 1.