Simultaneous microdetermination of nicardipine and its pyridine metabolite in body fluids by capillary column gas chromatography with electron-capture detection.
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Animals↗
Biomedical subjects
S Higuchi
Publications and source records attributed to S Higuchi.
G-CSF for chromosome analysis of myeloid leukemias and MDS.
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Colony-Stimulating Factors↗
Cloning and characterization of molecular isoforms of the catalytic subunit of calcineurin using nonisotopic methods.
The cloning and characterization of cDNAs for the catalytic subunit of calcineurin (CN) from murine and human brain libraries were carried out using nonisotopic methods. A murine cDNA clone encoding a protein of 521 amino acids (Mr approximately 58,650) was isolated; overlapping clones established a 3'-untranslated region of 554 base pairs preceding the poly(A) tail. Homologous cDNAs from human brain showed greater than 92% nucleotide sequence identity in both coding and non-coding regions with greater than 99% conservation of amino acid sequence. A second class of cDNAs lacking a specific 30-base pair region following the calmodulin-binding domain was found in four murine and human libraries. Oligonucleotide probes for both cDNA isoforms hybridized to mRNA from several brain regions indicating the existence of transcripts in vivo. The nucleotide sequences of the two forms were identical except for the inserted sequence, and Southern blot analysis of mouse and rat DNA was consistent with their having originated from the same gene; these data suggest that alternative splicing may give rise to molecular isoforms of the catalytic subunit in brain. Northern blots showed a predominant mRNA for CN in most tissues of approximately 4.0 kilobases (kb) with lower amounts of a 3.6-kb species. Brain showed 10 times more of these mRNAs than skeletal muscle while other tissues had less than or equal to 5% that in brain. In testis, multiple mRNAs were observed, with the major forms being approximately 2.8 and 1.6 kb; the total amount of CN message was about 15% that in brain. The presence of mRNA isoforms of the catalytic subunit may provide for isoenzymes of this phosphatase having distinct phosphoprotein substrate specificities or regulatory properties. The structural relatedness of CN to other mammalian serine/threonine protein phosphatases was highest over a region of approximately 240 amino acids near the amino terminus of this subunit, with greater similarity to protein phosphatase 2A than protein phosphatase 1. The conservation of many regions found in lambda phage phosphatase (Cohen, P.T.W., and Cohen, P. (1989) Biochem. J. 260, 931-934) indicates a common origin for the catalytic domain of this enzyme.
Amino Acid Sequence↗
Determination of mepirodipine in plasma by capillary column gas chromatography-negative-ion chemical ionization mass spectrometry.
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Calcium Channel Blockers↗
[Evaluation of the intra-hepatic arterial injection therapy of cisplatin (CDDP)-lipiodol suspension in a child with hepatoblastoma].
Treatment, beginning in November 1986, of chemotherapy with cisplatin (CDDP) was given to a 4-year-old girl with unresectable hepatoblastoma. Laparotomy for excision was performed after 16 months of therapy. The solution of CDDP was administered by dropping intravenously (DIV therapy) or intrahepatic arterially (IA therapy), and a suspension of crystalline CDDP with Lipiodol containing phosphatidylcholine was injected intrahepatic arterially (CDDP-suspension therapy). To evaluate the safety and effect of CDDP-suspension therapy in this case, toxicity and antitumor effect were investigated by comparison with DIV therapy. Under chemotherapy with CDDP, logarithm of alpha-fetoprotein reduced linearly. When a slope (k) of the regression line was defined as a constant of AFP reduction rate, k was -0.0072. AFP reduction rate under CDDP-suspension therapy (k = -0.0097, 12/1987-6/1988) was more rapid than that under DIV therapy (k = -0.0053, 2/1987-12/1987), and AFP reduced completely in June of 1988. The CDDP-suspension therapy may be suggestive of more effective treatment. Platinum (Pt) concentration in serum, urine and hepatic specimens was determined in order to investigate CDDP pharmacokinetics. The area under serum concentration (AUC) per doses and renal elimination rate were lower values under CDDP-suspension therapy. In the hepatic specimen, Pt concentration was significantly higher at the site where Lipiodol was localized. These results suggested that CDDP-suspension therapy delayed CDDP distribution and reduced toxicity. After CDDP-suspension therapy, reversible toxicity to the liver was observed. However, that to kidney or to blood components was less severe than after DIV therapy. After multiple DIV therapy, serum creatinine and blood urea nitrogen increased gradually in the course of therapy, while they tended to recovery after multiple CDDP-suspension therapy.
Carcinoma, Hepatocellular↗
A disease with immune deficiency, skin abscesses, pancytopenia, abnormal bone marrow karyotype, and increased sister chromatid exchanges: an autosomal recessive chromosome instability syndrome?
A 19-year-old girl is described with microcephaly, short stature, mental retardation, pigmentation of the skin, and recurrent skin abscesses over the whole body. Her elder brother and sister both showed growth and developmental retardation, microcephaly, and anemia. Both died during childhood. Their parents were first cousins. Laboratory studies of the proband revealed hyperchromic erythrocytes with an increased HbF content, thrombocytopenia, an impaired mitogenic response of the PHA-stimulated lymphocytes, and partial impairment of humoral and cellular immunity. She developed pancytopenia in the terminal stage of the disease. Cytogenetic studies of the bone marrow revealed 46,XX, 15p+, -18, +mar karyotype, increased chromosomal aberrations and sister chromatid exchanges, in cultured lymphocytes and skin fibroblasts. She died at age 20. Thus, the disorder in the patient was deduced as an unclassified chromosomal breakage syndrome with an apparently autosomal recessive inheritance.
Abscess↗
26,27-Hexafluoro-1,25-dihydroxyvitamin D3 (F6-1,25(OH)2D3) prevents osteoporosis induced by immobilization combined with ovariectomy in the rat.
The effect of 26,27-hexafluoro-1,25-dihydroxyvitamin D3 (F6-1,25(OH)2D3) on experimental osteoporosis in the rat induced by a combination of immobilization and ovariectomy was evaluated. F6-1,25(OH)2D3 increased the femur score and the photo-density. The administration of F6-1,25(OH)2D3 also significantly increased the dry weight, the ash weight and the ash content of the bone. Both F6-1,25(OH)2D3 and 1 alpha(OH)D3 showed a nearly dose-dependent effect and significant inhibition of the decrease of bone mass. Histomorphometry revealed a significant decrease of resorption by the administration of F6-1,25(OH)2D3. Bone formation rate in the F6-1,25(OH)2D3 treated group significantly decreased compared with the vehicle group. In conclusion, the pharmacological effective dose of F6-1,25(OH)2D3 was considered to prevent the osteoporotic decrease of bone mass by suppressing the elevated bone turnover.
Animals↗
Induction of endogenous lymphokine-activated killer activity by combined administration of lentinan and interleukin 2.
Lymphokine-activated killer activity in vivo (endogenous LAK activity) was found to be augmented by combined administration of lentinan, a beta (1-3) glucan with beta-1,6 branches, and interleukin 2 (IL-2). In contrast, addition of lentinan during culture in vitro did not augment LAK activity induced by IL-2. Surface marker analysis of endogenous LAK cells revealed that endogenous LAK cells induced by a combined administration of lentinan and IL-2 were all NK-type LAK cells, which express asialo-GM1 and lack T3, Thy-1 and Lyt2, whereas LAK cells generated in vitro were composed of both NK-type LAK and T-type LAK cells, which express T3 and Thy-1, and lack asialo-GM1. Furthermore, combined administration of lentinan and IL-2 was found to augment the endogenous LAK activity even in the tumor bearer, and show a substantial inhibition of tumor growth and a significant increase in survival rate in the C3H/HeN/MM46 system. Results of the present investigation offer a possible clinical application of a combination of lentinan and IL-2 for immunotherapy against cancer without detrimental side effects.
Animals↗
Genetic or cultural determinants of drinking: a study of embarrassment at facial flushing among Japanese and Japanese-Americans.
Facial flushing after the ingestion of alcohol is common among Asians. Flushers are genetically less able to tolerate alcohol than nonflushers and are less likely to become alcoholics. This study examined whether lower consumption of alcohol among flushers was correlated with cultural factors such as embarrassment over flushing as well as with biological factors among Japanese in Japan and Japanese-Americans using data from a joint Japan-U.S. collaborative survey. Eight hundred forty-six Japanese and 737 Japanese-American current drinkers with known flushing status were studied. The mean alcohol intake differed significantly between groups: (1) habitat--Japanese versus Japanese-Americans, (2) flushing status--flushers versus nonflushers, and (3) embarrassment about flushing. Among men, ethnicity was the major determinant of alcohol consumption, followed by flushing status and embarrassment about flushing. Among women, differences were not significant. Lower alcohol consumption by flushers than by nonflushers has been attributed to differences in physiological reactions to alcohol. However, this study demonstrated that cultural factors such as embarrassment also contribute to lower alcohol consumption by flushers. The lack of interaction between habitat and flushing status and between habitat and embarrassment status suggests that flushing status and embarrassment status associated with drinking levels are independent of habitat.
Adult↗
Analysis of the factors influencing anti-epileptic drug concentrations--carbamazepine.
The factors that influence carbamazepine (CBZ) serum concentrations and level:dose ratios were evaluated retrospectively on 83 consecutive routine CBZ determinations from chronically treated epileptic patients. The total level:dose ratio was lower when the drug was given in combination with phenytoin or with phenytoin plus other anti-epileptic drugs (AED) than when CBZ was given alone. The free level:dose ratio was also decreased during concomitant treatment with phenytoin. In spite of alterations to both level:dose ratios, the free fraction of CBZ was unaltered when in combination with other AEDs. There were statistically significant correlations between the CBZ dose (mg/kg/day) and the serum levels:total (r = 0.372, P less than 0.001) and free (r = 0.335, P less than 0.005). However, the wide scatter in the CBZ serum levels at each given dose were such that the relationships had no predictive values. Stepwise multivariate regression analysis (MVR) was also performed. A comparison of the normalized regression coefficients indicated that the CBZ dose, PHT dose, the time elapsed from the previous dose, the albumin concentration and the triglyceride levels were important factors which influence the CBZ total serum level. Similar analysis for the CBZ free serum level, gave a multiple correlation coefficient of 0.838, which indicates that 70.3% of the variance was explained by nine independent variables. The major factors that significantly affected the free serum level of CBZ were CBZ dose, PHT dose, the time elapsed from the previous dose and the triglyceride and albumin levels. Our observations indicate that it may be possible to predict reliably the CBZ serum concentrations for individual patients before institution of CBZ therapy.
Aging↗
Analysis of the factors influencing anti-epileptic drug concentrations--valproic acid.
The factors that influence valproic acid (VPA) serum concentrations and level:dose ratios were evaluated, retrospectively, on 51 consecutive routine VPA determinations from 50 chronically treated epileptic patients. The influence of co-medicated anti-epileptic drugs (phenytoin, phenobarbital, carbamazepine), alone or in combination, on total and free levels of VPA was studied. Furthermore, the possible influence of certain physiological and/or pathophysiological factors (age, weight, sex and clinical laboratory data) was considered. The total level:dose ratio was lower when VPA was given in combination with phenytoin or with carbamazepine than when VPA was given alone. The free level:dose ratio also decreased during concomitant treatment with phenytoin. The free fraction of VPA was unaltered when in combination with phenytoin or with carbamazepine, whereas it was decreased by a combination with phenytoin plus carbamazepine. As a whole, strong, positive, correlations existed between the VPA dose (mg/kg/day) and the total and free serum levels of VPA in the range of less than 15 mg/kg/day, but both levels of VPA tended to flatten out at the range of more than 15 mg/kg/day. These findings should therefore be considered when defining dosage regimens or interpreting serum drug concentrations. Stepwise multivariate regression analysis (MVR) showed that the VPA dose, simultaneous carbamazepine intake, serum glutamic oxalacetic transaminase (SGOT) and serum albumin concentration were important determinants of VPA serum concentrations.
Adolescent↗
Therapeutic drug monitoring services at Kyushu University Hospital in Japan.
Quantitative evaluation of the therapeutic drug monitoring services (TDMS) provided in Kyushu University Hospital from August 1981 to April 1989 was performed. Since 1982, the annual number of assay requests was about 4300-4400, but the annual number of clinical pharmacokinetic consultation services (CPCS) showed a tendency to increase. Antiepileptics were the drugs for which CPCS were most often performed (26.3 percent of the population given drugs for which TDMS was available); digoxin, lithium, and theophylline followed. Preparation of one consultation required 1.5-2.5 hours. Our TDMS team consists of eight members. In 1988, the average time per week spent for CPCS and TDMS was 8.2 and 11.3 hours per member, respectively. Thus, the number of pharmacists performing CPCS and TDMS was 1.2 and 1.7 full-time equivalents, respectively.
Drug Information Services↗
Effect on carbon lengthening at the side chain terminal of 1 alpha,25-dihydroxyvitamin D3 for calcium regulating activity.
A series of analogs of 1 alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3 (1)] with alkyl substitutions in 26- and 27-positions have been tested for their activity 1) in competing with 1,25-(OH)2D3 for binding to chick intestinal cytosol receptor, 2) in ability for formation of multinucleated cells (MNC) with various osteoclastic cell characteristics from blast cells, and 3) in stimulating bone calcium mobilization in vitamin D-deficient rats. The relative potencies of 1,25-(OH)2D3, 1 alpha,25-dihydroxy-26,27-dimethylvitamin D3 (2), 1 alpha,25-dihydroxy-26,27-diethylvitamin D3 (3), and 1 alpha,25-dihydroxy-26,27-dipropylvitamin D3 (4) in competing for intestinal cytosolic binding were 1:1.1:0.25:0.05. The similar order of the abilities on formation of the multinucleated cells in the same series was observed. In a bone calcium mobilization test with vitamin D-deficient rats, 1 alpha,25-dihydroxy-26,27-dimethylvitamin D3 showed slightly less activity than 1,25-(OH)2D3 at 12 h after administration, but long lasting activity was observed during time course experiments. 1 alpha,25-Dihydroxy-26,27-diethylvitamin D3, and 1 alpha,25-dihydroxy-26,27-dipropylvitamin D3 were found to be much less active than 1,25-(OH)2D3 in a bone calcium mobilization test.
Animals↗
Population pharmacokinetics of phenytoin from routine clinical data in Japan: an update.
Routine clinical pharmacokinetic data collected from outpatients receiving phenytoin (PHT) were reanalyzed to estimate population pharmacokinetic parameters. There were 756 steady-state PHT concentrations and associated dosage rates (mg/d) from 334 outpatients. The data were analysed using nonlinear mixed effects model (NONMEM), a computer program designed for population pharmacokinetic analysis that allows pooling of data from many individuals. The influence of weight, co-anticonvulsants on the maximum elimination rate (Vm) and age, co-anticonvulsants on the Michaelis-Menten constant (Km) and the influence of dosage form on the bioavailability (F) of PHT were investigated. The Vm and Km of a 60 kg adult outpatient treated with PHT alone were estimated to be 325 mg/d and 2.41 micrograms/ml, respectively, while for a same size individual taking PHT with co-anticonvulsants respective estimates were 351 mg/d and 3.18 micrograms/ml. The parameter of a power function of weight was estimated to adjust Vm for body size. The best function adjusts Vm in proportion to weight to the 0.737 power. The Km for patients less than 15 years old was 24.8% less than that of adults. Assuming the F of PHT to be 1 in patients prescribed a tablet, the F value in patients prescribed a powder was [1-exp(-9.92/Dij)]; Dij is the daily dose of PHT for the ith Cpss in the jth patients (mg/kg/d).
Adolescent↗
Efficacy of emetic and United State pharmacopoeia ipecac syrup in prevention of drug absorption.
The efficacy of both the emetic syrup prepared in the previous report and the United States Pharmacopoeia (USP) ipecac syrup concerning the prevention of drug absorption was investigated in 4 beagle dogs using a randomized and cross-over design. In order to control the intragastric pH of the beagle dogs, the administration of pentagastrin or hydrochloric acid (HCl)-glycine buffer (pH 1.5) was tested. The intragastric pH changed from 7.2 to 1.8 with the intramuscular administration of pentagastrin, but the primary emesis occurred more slowly. On the other hand, the HCl-glycine buffer (pH 1.5) gave the appropriate emesis. Therefore, the HCl-glycine buffer (pH 1.5) was used to control the intragastric pH of the beagle dogs. Acetaminophen (AcA), salicylic acid (SA) and kanamycin (KM) as markers were administered orally after conditioning the intragastric pH at 1.5. The emetic syrup or the USP ipecac syrup was then administered. The recovery rate of AcA and KM from vomit was 42-65%. The emetic syrup and the USP ipecac syrup significantly reduced the absorption of AcA from the calculation of pharmacokinetic parameters compared to the control syrup. It was observed that the absorption of cephaeline (CP) in the emetic syrup was less than that of CP in the USP ipecac syrup.
Absorption↗
Estimation of the molecular volumes of the reaction products between beta-lactam antibiotics and aminoglycoside antibiotics, and those of the degradation products of beta-lactam antibiotics by isotachophoresis.
The correlative equations between the molecular volume and the qualitative indication (hR) for beta-lactam antibiotics, the reaction products between beta-lactam antibiotics and kanamycin, and the degradation products of beta-lactam antibiotics were hR = 0.32 + 0.080 VA2/3//Z/(N = 15, r = 0.972 for penicillins) and hR = 0.04 + 0.072 VA2/3//Z/(N = 12, r = 0.987 for cephems). Where VA is van der Waals volume (A3/molecule), hR is the relative step height in the isotachopherogram, and Z is the electric change, respectively. According to these equations, the molecular volumes of the reaction products between beta-lactam antibiotics and the other aminoglycoside antibiotics, and those of the degradation products of beta-lactam antibiotics can be estimated from the value of hR. Also according to the step height in the isotachopherogram, the reaction products or the degradation products may be estimated directly when the electric charge is known. It was confirmed that a molecule of aminoglycoside antibiotics reacted with a molecule of beta-lactam antibiotics. Therefore, the inactivation of aminoglycoside antibiotics is much greater than for beta-lactam antibiotics when the clinical doses of these antibiotic combinations are used.
Aminoglycosides↗
Phenytoin dosage adjustment method using population clearance.
Phenytoin (PHT) is a commonly used drug in children and adults, but it is often difficult to adjust the dosage to attain therapeutic drug concentrations due to the nonlinear nature of PHT metabolism. Therefore, many techniques have been proposed to aid dosage adjustment based on single-point PHT concentration determined at the steady state. We have derived a simple equation to predict PHT dosage in a patient in whom one steady-state serum concentration is known. This equation is based on a power relationship between PHT clearance (CL; 1/d) and PHT concentration determined at the steady state (Css; micrograms/ml). CL = D/Css = a.Css(b) (1) Dn = Do.Co-(b+1).Cd(b+1) (2) where D is the PHT dose (mg/d), Do is the original dose, Dn is the new dose, Co is the original Css, and Cd is the desired Css. We retrospectively investigated the values of a and b in a population of 40 outpatients who had three or more reliable measurements of Css in serum, measured while they were taking different daily doses. The a and b values were estimated to be 114.34 and -0.6786, respectively (n = 126; r = 0.871). Graves et al. have previously derived a similar equation based on an exponential relation between CL of PHT and Css in 59 patients (a = 133.03, b = -0.804). The predictive ability of this equation was compared with the results of Graves's method and the Bayesian feedback method using retrospective data from 70 patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Studies on topical antiinflammatory agents. V. 17-(Alkylthio)- and methoxyalkanoates of corticosteroids.
As part of our search for new topical antiinflammatory agents, a series of corticosteroid 17-(alkylthio)- and methoxyalkanoate derivatives was prepared and tested for vasoconstrictive activities. Several compounds were proved to have activity superior or comparable to that of 9 alpha-fluoro-11 beta,21-dihydroxy-16 beta-methyl-17 alpha-valeryloxy-1,4-pregnadiene-3,20-dione (betamethasone 17-valerate, BV). Among these compounds, 21-chloro-11 beta-hydroxy-17 alpha-(methylthio)acetoxy-4-pregnene-3,20-dione (5Aa) was found to have the most potent activity, being more active than BV. The structure-activity relationships of the series revealed that introduction of a (methylthio)acetate function into the 17-position as well as the 21-position of corticosteroids was effective for enhancing the topical antiinflammatory activity.
Administration, Topical↗