Database study of antibiotic resistant tuberculosis in the United Kingdom, 1994-6.
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Adolescent↗
Biomedical subjects
M Chadwick
Publications and source records attributed to M Chadwick.
Liquid chromatographic analysis in mouse, dog and human plasma; stability, absorption, metabolism and pharmacokinetics of the anti-HIV agent 2-chloro-5-(2-methyl-5,6-dihydro-1,4-oxathiin-3-yl carboxamido) isopropylbenzoate (NSC 615985, UC84).
NSC 615985 (UC 84) has demonstrated anti-HIV activity in the NCI-AIDS antiviral screen and was under consideration as an anti-AIDS drug. The compound was subsequently shown to be a non-nucleoside reverse transcriptase inhibitor (NNRTI). An HPLC method was developed for the analysis of NSC 615985 in mouse, dog and human plasma; and was used to study its stability in plasma and blood as well as its absorption and metabolism in mice. The method involved precipitation of plasma protein with three volumes of methanol followed by HPLC analysis of the supernatant. The HPLC analysis was carried out on a reversed-phase Nova-Pak C18 column with a mobile phase of KH2PO4 (0.01 M; pH 4.8)-acetonitrile (52:48, v/v) at a flow rate of 1 ml min-1 and quantification with a UV detector set at 259 nm. The lower limit of quantitation was 0.05 microgram ml-1 in 1 ml of dog or human plasma or 0.1 microgram ml-1 in 0.5 ml of mouse plasma. NSC 615985 was more stable in dog and human plasma than in mouse plasma, and was less stable in blood than in plasma of the three species investigated. Following bolus intravenous (i.v.) administration at 10 mg kg-1 to male CDF1 mice, NSC 615985 elimination followed biexponential kinetics with half-lives of 1 and 7 min, and was extensively metabolized. NSC 615985 was very poorly absorbed following oral (PO) administration as a suspension in water or in 20% lipid emulsion (Liposyn II). Following bolus subcutaneous (s.c.) administration of [14C]NSC 615985 at 10 mg kg-1, relatively low concentrations of the parent compound were observed in three of 36 mice. One metabolite was tentatively identified in plasma of both the i.v.- and s.c.-treated animals as the sulfoxide of the parent compound. No parent compound was detected in the urine of NSC 615985 dosed mice. At least seven metabolites were present in urine; one metabolite (constituting 8-14% of urinary radioactivity) was tentatively identified as the carboxylic acid resulting from the hydrolysis of the isopropyl group from the parent compound. In summary, NSC 615985 was poorly absorbed following oral administration and extensively metabolized and eliminated following i.v. or s.c. administration. This unfavorable pharmacokinetic profile of NSC 615985 as well as its pattern of activity against NNRTI-resistant strains of HIV-1 precluded its progression to clinical trial; however, other members of the general chemical class are currently being evaluated by the NCI.
Animals↗
Towards improved knowledge sharing: assessment of the HL7 Reference Information Model to support medical logic module queries.
Because clinical databases vary in structure, access methods and vocabulary used to represent data, the Arden Syntax does not define a standard model for querying databases. Consequently, database queries are encoded in ad hoc ways and enclosed in "curly braces" in Medical Logic Modules (MLMs). However, the nonstandard representation of queries impairs sharing of MLMs, an impediment that has come to be known as the "curly braces problem." As a first step in solving this problem, we evaluated the proposed HL7 Reference Information Model (RIM) as a foundation for a standard query model for the Arden Syntax. Specifically, we analyzed the MLM knowledge base at the Columbia-Presbyterian Medical Center and compared the queries in these MLMs to the RIM. We studied 488 queries in 104 MLMs, identifying 674 total query data elements. Laboratory tests accounted for 45.8% of these elements, while demographic and ADT data accounted for 37.6%. Pharmacy orders accounted for 10.5%, medical problems for 4.3% and MLM output messages for 1.6%. We found that the RIM encompasses all but those data elements signifying MLM output (1.6% of the total). We conclude that the majority of queries in the CPMC knowledge base access a relatively small set of data elements and that the RIM encompasses these elements. We propose extensions of this analysis to continue construction of an Arden query model capable of solving the "curly braces problem."
Artificial Intelligence↗
NMR-based structural studies of the pNR-2/pS2 single domain trefoil peptide. Similarities to porcine spasmolytic peptide and evidence for a monomeric structure.
NMR spectroscopy measurements have been used to obtain structural information about the pNR-2/pS2 single-domain trefoil peptide. NMR data from 2D (two dimensional) double-quantum-filtered correlation spectroscopy (DQF-COSY), total correlation spectroscopy (TOCSY), NOE spectroscopy (NOESY), rotating frame NOE spectroscopy (ROESY) and 2D 13C-1H heteronuclear single-quantum coherence (HSQC) and 13C-1H HSQC-TOCSY spectra have been analysed to provide essentially complete 1H and 13C sequence-specific assignments for the pNR-2/pS2 protein. From a consideration of the NOE intensities, 3J(NH-alpha CH) coupling constants, 1H and 13C chemical shifts of backbone atoms and amide-proton exchange rates, the pNR-2/pS2 was found to contain two short antiparallel beta-strands (32-35 and 43-46), a short helix (25-30) and a type I beta-turn (11-15). These elements of secondary structure are very similar to those found in the two trefoil domains of pSP for which detailed structural information is already available. Similar 1H chemical shifts were noted for several conserved residues in pNR-2/pS2 and pSP and a characteristic Phe residue with a slowly flipping ring was found in the pNR-2/pS2 variant and in both domains of pSP. The tertiary structures of the domains therefore appear to be very similar in the two proteins and it is likely that the pNR-2/pS2 has the same pattern of disulphide bonds (1-5, 2-4, 3-6) as pSP. Correlation time measurements derived from 1H-1H NOE measurements indicate that the Cys58-->Ser form of the pNR-2/pS2 protein used in this study is monomeric in solution at approximately 2 mM.
Amino Acid Sequence↗
Comparative disposition of 2,3-epoxy-1-propanol (glycidol) in rats following oral and intravenous administration.
Glycidol (2,3-epoxy-1-propanol), an industrial chemical, has been shown to be a reproductive toxicant in short-term studies and a carcinogen in rats and mice in oncogenicity studies. The reproductive toxicity of glycidol was believed to result from its conversion to alpha-chlorohydrin by the action of HCl in the stomach. The comparative disposition of glycidol was investigated in rats following oral (po) or intravenous (iv) administration at doses of 37.5 and 75 mg/kg. These were the doses used in the National Toxicology Program (NTP) oncogenicity study with glycidol. Approximately 87-92% of the dose was absorbed from the gastrointestinal tract of the rat. [14C]Glycidol equivalents were eliminated in urine (40-48% of dose in 72 h), feces (5-12%), and exhaled as CO2 (26-32%). At both doses, 9-12% and 7-8% (estimated) of the dose remained in tissues at 24 and 72 h following dosing, respectively. In general, the concentrations of glycidol equivalents in tissues were proportional to the dose. The highest concentrations of radioactivity were observed in blood cells, thyroid, liver, kidney, and spleen, and the lowest in adipose tissue, skeletal muscle, and plasma. The pattern of distribution of radioactivity in tissues was similar for both the iv and po routes. The total recovery of radioactivity ranged from 87 to 91% of dose. Urinary radioactivity was resolved by high-performance liquid chromatography (HPLC) analysis into 15 metabolites. There were one major (14-21% of the dose) and four lesser metabolites (each representing 2-8%); the others were minor, each representing 1% or less of the dose. In general, the urinary metabolic profile was similar following either iv or po administration at the two doses studied. Previous studies by other investigators suggested that alpha-chlorohydrin, which was presumably formed from glycidol by the HCl in the stomach, was metabolized and excreted in urine as beta-chlorolactic acid. The results of the present study show that very little, if any, urinary radioactivity coeluted with authentic beta-chlorolactic acid following either iv or po administration. Therefore, it is concluded that the conversion of glycidol to alpha-chlorohydrin is quantitatively insignificant. However, it may be significant with regard to glycidol reproductive toxicity. Also, the NTP oncogenicity study with glycidol was carried out within the dose range in which its disposition characteristics were linear.
1-Propanol↗
Pulmonary absorption and disposition of [14C]thiophene in rats following nose-only inhalation exposure.
The absorption, disposition, and metabolism of [14C]thiophene was investigated in rats following nose-only inhalation exposure at 8000 ppm for 1 h. Under these exposure conditions, it was estimated that approximately 16.3% (493 mumol) of the inhaled thiophene was absorbed from the respiratory system. Within 72 h following exposure, a total of 488 mumol of thiophene equivalents (99% of that retained) was excreted, of which 360.4 mumol (73.9% of the total excreted radioactivity) was in expired air, 120.7 mumol (24.8%) was in urine, 3 mumol (0.6%) was in feces, and 3.7 mumol (0.8%) was in the cage wash. Excretion took place primarily within the first 8 h, during which 91% of the total radioactivity excreted was collected. The thiophene equivalents remaining in tissues at 72 h were estimated to total 5.1 mumol (1.0% of the retained radioactivity). Exhaled radioactivity was identified as thiophene. No 14CO2 was detected in the expired air. After 1 h following exposure, the elimination of thiophene equivalents from plasma was monophasic, with a half-time of 3.6 h. The elimination of thiophene equivalents from blood cells was biphasic, with half-times of 2.9 h and 9.1 d. The blood cells/plasma concentration ratios of thiophene equivalents ranged from 3 to 13, with the higher ratio observed at the 12-h time interval. At 72 h after exposure, blood cells contained the highest concentration of thiophene equivalents, approximately fourfold higher than that of the liver, which contained the second highest concentration. Kidney, heart, and lung contained similar but lower concentrations than liver, while brain, fat, and skeletal muscles contained the lowest concentrations. In summary, this study demonstrates that thiophene was absorbed from the respiratory system, and the majority of the absorbed thiophene was eliminated unchanged in the exhaled air, while a smaller fraction was metabolized and eliminated in urine.
Absorption↗
Combination chemotherapy with ciprofloxacin for infection with Mycobacterium tuberculosis in mouse models.
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Animals↗
Preclinical antitumor activity and pharmacological properties of deoxyspergualin.
A new antibiotic, deoxyspergualin (DSG), demonstrated antitumor activity against L1210 leukemia in mice. The life span of mice bearing either i.p. or s.c.-implanted L1210 increased greater than 150% following i.p. administration of 25 mg/kg DSG on days 1-9. Activity obtained with i.p. bolus treatments was schedule dependent. The tumor burden in mice bearing the s.c. implanted L1210 was reduced by 4-6 log10 units at the end of treatment when DSG was administered every 3 h for 8 injections on days 1, 5, and 9. By contrast, single injections of DSG on days 1, 5, and 9 allowed the tumor burden to increase at least 100-fold during treatment and daily single injections for 9 days reduced the tumor burden by 2 log10 units. The therapeutic advantage for i.p.-implanted L1210 of maintaining plasma concentrations of DSG was indicated further by infusion studies using s.c.-implanted Alzet osmotic pumps. Tumor burden was reduced by 3.5 and 6 log10 units following s.c. bolus treatments every 3 h on day 1 and a 24 h-infusion, respectively. The optimal infusion time for an infusion rate in mice of 179 mg/kg/day appeared to be 72 h. Pharmacokinetic studies following bolus i.v. injection revealed a rapid plasma clearance of parent drug (20.8 ml/min/kg) and a beta half-life of approximately 12 min. The bolus dose kinetics was used to predict the steady state plasma concentrations resulting from s.c. infusion; good agreement was observed between predicted values and experimental results. Based on these preclinical data, DSG has been developed to clinical trial. Initial Phase I protocols involve a 120-h infusion schedule.
Administration, Oral↗
Use of gas liquid chromatography in the clinical diagnosis of anaerobic pleuropulmonary infection.
Evidence of anaerobic infection was sought in 83 patients with pulmonary disease with anaerobic culture and gas liquid chromatography (GLC) of mucopurulent sputum, or pleural fluid where appropriate. Saliva samples from nine healthy controls and 14 patients with cystic fibrosis were examined by the same methods to assess anaerobic content. Clinically significant anaerobic pleuropulmonary infection was not found in our patients with bronchitis, bronchiectasis and cystic fibrosis and occurred in only some of our patients with empyema and lung abscess. GLC of pleural fluid (empyema) or sputum (lung abscess) was helpful in identifying these cases, when a strongly positive reading was obtained. The gas liquid chromatogram was negative or only weakly positive in those patients where the presence of anaerobes was clinically insignificant, most probably resulting from contamination of the sputum samples by saliva. Results were rapidly available and the need for transtracheal aspiration to obtain specimens of bronchial secretion uncontaminated by mouth flora was avoided. The semiquantitative GLC would therefore appear to be a useful method for investigating specimens from patients with suspected anaerobic pleuropulmonary infection.
Adult↗
Local area networks and the hospital.
Hospital information systems are characterized by their complexity of individual functions, heterogeneity of functions, and dependence upon integration. A distributed computerized information system is well suited to meeting the needs of hospitals. A local area communications network (LACN) removes a major impediment to the use of distributed systems. An advanced microprocessor-based LACN using fiberoptic communications has been developed by the Applied Physics Laboratory of The Johns Hopkins University and has been implemented at the University of California, San Francisco Hospital.
California↗
A phase I trial of combination therapy with continuous-infusion PALA and continuous-infusion 5-FU.
Thirty-four patients were treated with N-(phosphonacetyl)-L-aspartate (PALA) at a dose of 850 mg/m2/day x 5 by continuous intravenous infusion (days 1-5) and 5-fluorouracil (5-FU) on an escalating dose schedule of 300-630 mg/m2/day x 5 by continuous intravenous infusion (days 2-6). Dose-limiting oral mucositis occurred at a 5-FU dose of 560 mg/m2/day; other toxicities included nausea, vomiting, diarrhea, skin rash, and superficial venous phlebitis. Myelosuppression was rare. One partial response was observed in a patient with metastatic colorectal carcinoma. Plasma PALA levels were monitored in seven patients. Steady-state levels were achieved by the 2nd day of drug infusion and ranged between 10 and 20 micrograms/ml.
Adult↗
Comparative physiological disposition of N-(phosphonacetyl)-L-aspartate in several animal species after intravenous and oral administration.
The physiological disposition of N-(phosphonacetyl)-L-aspartate (NSC 224131; PALA), a potent inhibitor of aspartate transcarbamylase, has been studied in mouse, rat, dog, and monkey after administration of [14C]PALA at 120 mg/sq m i.v. or p.o. Concentrations of PALA equivalents in plasma, urine, and feces were determined radiochemically, and urine was analyzed chromatographically for PALA. The disposition of PALA equivalents in mouse tissues was determined radioautographically. After i.v. administration, PALA was rapidly (half-time, approximately 1 hr) and extensively (up to 80% of the dose) excreted in the urine of all species. Less than 5% was excreted in the feces. Only PALA was found in the urine of all four species, indicating that the metabolism of PALA, if it occurs at all, is insignificant. PALA equivalents were poorly taken up by mouse tumors and tissues, except kidney, bone, and to a lesser extent, skin and lung, and were rapidly and extensively cleared from all except bone. No differences were apparent in the uptake of PALA equivalents by Lewis lung carcinoma (sensitive to PALA treatment) and L1210 lymphocytic leukemia (insensitive). The pharmacokinetics of PALA in the plasma of rat, dog, and monkey, as well as mouse, were inconsistent with deposition of PALA in tissues and more consistent with the probable distribution of PALA into extracellular water. PALA equivalents were eliminate from all species at a rate (half-time, 1 to 1.5 hr) reflecting the rate of urinary excretion of the drug and at a secondary slower rate probably reflecting the rate of release of bound PALA from sites such as aspartate transcarbamylase. PALA was poorly absorbed into the systemic circulation when administered p.o., in that mouse, rat, and monkey excreted less than 5% of the dose in the urine after p.o. administration. These data on the physiological disposition of PALA explain why high doses of the drug have to be administered to achieve therapeutic and toxic effects, despite the inhibitory potency of the drug on aspartate transcarbamylase. They indicate that PALA will be ineffective administered p.o. and might be contraindicated in patients with impaired renal function and that the kinetics of aspartate transcarbamylase-bound drug is probably more important in determining dose scheduling than the kinetics of free PALA.
Administration, Oral↗
Long-term association of N-(phosphonacetyl)-L-aspartate with bone.
By means of enzymatic and autoradiographic techniques, it has been demonstrated that, 24 hr after a single dose of the antitumor amino acid N-phosphonacetyl-L-aspartic acid (PALA), (400 mg/kg i.p.; 1.15 mmol/kg) to C57BL x DBA/2 F1 mice, the agent accumulates in bone to a concentration of approximately 400 microM; this is 3000 times greater than the Ki of PALA for its target enzyme, aspartate carbamoyltransferase. However, disproportionately low inhibition of enzyme activity was demonstrated in homogenates of bone from these recipients, suggesting that the drug was sequestered from its target in this tissue. Autoradiography of sections of femoral shafts from mice treated with 14C-labeled drug demonstrated that autoradiogram density due to [14C]PALA equivalents was confined to the bony matrix, with no label above background resolvable in bone marrow. Following in vivo administration of PALA (400 mg/kg i.p.), the half-life of the drug in the bone was approximately 23 days. In vitro, with equilibrium dialysis at pH 7.4, it was demonstrated that: (a) normal pulverized and decalcified bone bound PALA with capacities of 3.5 nmol/mg and 0.1 nmol/mg bone, respectively, at a PALA concentration of 5 mM; (b) binding of PALA to normal bone reached saturation at a concentration of 200 mM; and (c) PALA functions as a solubilizer of bone at concentrations above this. Since administration of PALA was shown to produce long-lasting inhibition of aspartate carbamoyltransferase in liver and tumor and since its ultimate half-life in the plasma of mice, following a single 400-mg/kg administration of the drug, is 8 days, it is suggested that bone serves as a reservoir from which PALA is released at a slow rate into plasma and other tissues.
Animals↗
Quantitation of the antitumor agent N-(phosphonacetyl)-L-aspartic acid in human plasma and urine by gas chromatography-mass spectrometry-selected ion monitoring.
N-(Phosphonacetyl)-L-aspartic acid (PALA) is an antitumor agent which is currently under clinical study. A gas chromatography--mass spectrometry--selected ion monitoring assay procedure using [13C]PALA as the internal standard has been developed for the quantitation of PALA in biological samples. Standard curves which related ion intensity peak height ratios (m/e 220/221) to PALA concentrations in plasma and urine were described by a non-linear least square analysis with correlation coefficients of R2 greater than 0.995 and greater than 0.996, respectively. Over concentration ranges for PALA of 1--60 micrograms/ml of plasma and 1--160 micrograms/ml of urine the coefficient of variation from the fitted curve was 4--18%. This methodology has been used to quantitate PALA in human plasma samples in a study on the clinical pharmacology of the drug.
Antineoplastic Agents↗
A study of infective and other factors in exacerbations of chronic bronchitis.
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Adult↗
Acupuncture treatment of cats.
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Acupuncture Therapy↗
Dichloroallyl lawsone.
Dichloroallyl lawsone (DCL, NSC-126771), a synthetic analogue of the antimalarial lapachol, is potentially useful in cancer chemotherapy. Unlike most anticancer agents, DCL is not significantly myelosuppressive in animals but it induces acute cardiac toxicity in the rhesus monkey. This cardiac toxicity seems to be correlated with the maximal plasma DCL concentration, about 130 mg/L in the monkey. We have studied DCL pharmacokinetics in patients in an attempt to define safe dose limits for the Phase I clinical trial. After the rapid intravenous infusion of 10 mg/m2 of radioactive [1- or 4-14C]DCL, 250 muCi per patient, the mean peak plasma concentration of unchanged DCL in four patients was 2.9 +/- 0.3 mg/L. The drug had a mean initial plasma half-life of 48.9 +/- 19 min and a terminal half-life of 20.3 +/- 1.8 hr, with a C X t of 50.1 +/- 12 mg/L/hr, and a clearance rate of 0.08 ml/kg/min. These data suggest that in clinical trials the DCL dose given by rapid intravenous infusion should not exceed 450 mg/m2 so that the maximal plasma drug concentration remains below 130 mg/L.
Antineoplastic Agents↗
Comparative physiologic dispositions of 5-fluoro-2'-deoxyuridine and 5-fluorouracil in mice bearing solid L1210 lymphocytic leukemia.
The physiologic disposition of 5-fluoro-2'-deoxyuridine (FUdR) and its metabolites, in particular the postulated active metabolite, 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), has been studied in BDF1 mice bearing 6-day solid L1210 lymphocytic leukemia between 2 and 72 hours after a single iv dose of 14C-2-FUdR at 380 or 760 mg/kg (400-1300 microcuries/kg). FUdR itself was rapidly eliminated from tissues by urinary excretion and metabolism. However, its metabolites, including 5-fluorouracil (FU), persisted for 72 hours in the acid-soluble and -insoluble fractions of tissues. In tumor and small intestine, 60% of the 0- and 72-hour exposure to FdUMP, based on the area under the concentration-time curve, occurred between 24 and 72 hours after dosing. The results are compared with the physiologic disposition of FU after administration at 200 mg/kg iv which is an equimolar dose to FUdR at 380 mg/kg and approximately equitoxic to FUdR at 760 mg/kg. The molar concentrations of total drug equivalents, and of FU itself, after FUdR at 760 mg/kg were comparable to those after FU. However, the concentrations of FdUMP were lower than after FU, whereas the concentrations of drug equivalents incorporated into the acid-insoluble fraction, which includes equivalents incorporated into RNA, were generally higher than after FU. These data are correlated with the comparative antitumor effects and toxicity in mice of the fluorinated pyrimidines and with their clinical effectiveness.
Animals↗