Teenage procyclidine abuse.
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Adolescent↗
Biomedical subjects
J Caldwell
Publications and source records attributed to J Caldwell.
Comparison of serum and cerebrospinal fluid levels of methotrexate in man during high-dose chemotherapy for aggressive non-Hodgkin's lymphoma.
The relationship between plasma and cerebrospinal fluid levels of methotrexate was studied in five patients, four with aggressive non-Hodgkin's lymphoma and one with mixed epithelial mesothelial tumour, who were treated with high-dose methotrexate (1.5 g/m2) as part of combination chemotherapy. Cerebrospinal fluid was sampled for 24 h via a permanent indwelling lumbar catheter. No complications were observed with this technique. In two patients with central nervous system involvement adequate "cytotoxic" levels (greater than 10(-6) M) were obtained for greater than 12 h. The remaining three patients, with no direct evidence of central nervous system involvement, never attained adequate cytotoxic methotrexate levels in the cerebrospinal fluid. Serum levels were therapeutic in all patients. These results suggest that patients with central nervous system tumour involvement may receive adequate doses of methotrexate in the cerebrospinal fluid. Patients with occult central nervous system tumour involvement may not attain adequate cerebrospinal fluid levels. A 24-h serum methotrexate level of greater than 10(-5) M may indicate that patients have achieved therapeutic cerebrospinal fluid levels of methotrexate. Cranial irradiation following chemotherapy is still recommended in this tumour group until adequate cytotoxic levels of methotrexate can be obtained in all patients for prolonged periods.
Adult↗
Comparative immunogenicity and protective effect against dental caries of a low (3800) and a high (185,000) molecular weight protein in rhesus monkeys (Macaca mulatta).
The immunogenicity and protective effect of two peptides derived from the human oral bacterium Streptococcus mutans (serotype c) was examined. Furthermore, the effect of immunization was examined in monkeys previously given fluoride in their diet and which had developed a low incidence of dental caries when offered a human type of diet containing about 15 per cent sucrose. The 3800 peptide streptococcal antigen (SA) has two major antigenic determinants, similar to those in the 185,000 SA I/II. Immunization with 10 (or 1) micrograms of the 3800 SA, made up in an aluminium-hydroxide adjuvant, induced a consistent increase in serum IgG, IgM and IgA antibodies to SA I/II throughout the period of investigation. Salivary-IgA antibodies were only slightly raised. Sequential examination up to 76 weeks showed a significantly lower incidence of dental caries and a lower proportion of Strep. mutans in the immunized compared with sham-immunized, control monkeys. Thus immunization with the 185,000 or 3800 SA can almost completely prevent dental caries in rhesus monkeys which otherwise develop a low incidence of caries.
Animals↗
The Jovian stratosphere in the ultraviolet.
The center-of-disk reflectivity of Jupiter in the wavelength range from 1450 to 3150 angstroms has been computed from 30 low-dispersion IUE spectra taken during solar maximum in 1978-1980. A vertically inhomogeneous radiative transfer program is used to compute model reflectivities of various stratospheric compositions for comparison. Ammonia and acetylene are well determined because they show narrow absorption bands in the ultraviolet. Above 1800 angstroms, these two gases provide a good fit to the data, but not below. At shorter wavelengths the fit would be much improved by a small amount (0.5-1.5 ppb) of propadiene/allene (C3H4). Voyager IRIS spectra show that the IR bands of allene are not strong enough to be detected in such a small amount. Additional absorption around 1600 angstroms can be reproduced best with the presence of cyclopropane (C3H6, <15 ppb), although other absorbers (e.g., hydrocarbon molecules with more than three carbon atoms, oxygen- or nitrogen-containing molecules, or a high-altitude haze) could also explain the spectrum in this region. The data are too noisy to detect possible CO Cameron band absorption near 2000 angstroms.
Acetylene↗
Influence of dose and sex on the disposition and hepatic effects of cinnamyl anthranilate in the B6C3F1 mouse.
Cinnamyl anthranilate is a synthetic food flavouring and fragrance agent, formerly used at very low levels. There is currently some concern over the potential risk to man from its use, since it has been found to cause liver tumours in mice, following the administration of very large doses. This paper reports studies of its disposition and hepatic effects in B6C3F1 mice in relation to dose. Following a single oral dose of 500 mg cinnamyl anthranilate/kg body weight to B6C3F1 mice peak plasma levels of unchanged compound were reached in 30 min, and were higher in males than in females. Unchanged cinnamyl anthranilate in the urine accounted for 0.3-0.4% of the dose. Anthranilic acid (c. 17%) and hippuric acid (35%; the major metabolite of cinnamyl alcohol) were present in the urine, and recoveries of both were higher in females. Groups of male and female B6C3F1 mice were given 0, 10, 100, 1000, 5000, 15,000 and 30,000 ppm cinnamyl anthranilate in the diet. After 4 days, the diet was removed and urine collected for 24 hr. This contained cinnamyl anthranilate (more in males) hippuric and anthranilic acids (more in females) in concentrations that increased with dose. Other animals were given these diets for 19 days and then killed. Relative liver weight and hepatic microsomal cytochrome P-450 increased with increasing dose above 1000 ppm cinnamyl anthranilate, more markedly in males than in females although the maximum response (roughly twofold) was very similar in the two sexes. SDS-PAGE examination of the microsomes revealed the induction of a cytochrome P-450 isozyme of 53.1 kDa, but the aniline hydroxylase and p-nitroanisole O-demethylase activities of the 9000 g supernatant of liver were not induced. The data are discussed in terms of their significance for the human safety evaluation of cinnamyl anthranilate. It is important to note that liver hypertrophy, microsomal enzyme induction and the excretion of unchanged cinnamyl anthranilate all have the same dose-threshold for their appearance. This suggests that the hepatic effects of cinnamyl anthranilate may be mediated by unhydrolysed cinnamyl anthranilate, which is present only at very high doses due to the saturation of its hydrolysis.
Animals↗
Novel xenobiotic-lipid conjugates.
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Alcohols↗
The metabolic chiral inversion of 2-arylpropionic acids--a novel route with pharmacological consequences--a correction.
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Biotransformation↗
Comparative pharmacokinetics of theophylline and ethylenediamine following single and repeated doses of a sustained-release aminophylline preparation to volunteers.
Plasma concentrations of theophylline and ethylenediamine have been measured by HPLC after a single dose and also after a further four consecutive doses at 12 h intervals of a tablet containing 225 mg aminophylline in a sustained release matrix (Phyllocontin) had been taken by volunteers. A dissolution study of the product showed the release of theophylline to follow zero-order kinetics, to be independent of bath pH, and to be complete in 6.5 h, while the release of ethylenediamine depended upon the pH of the medium and was more extensive in acid solutions. After one tablet, the plasma theophylline concentrations reached a maximum of 4 micrograms ml-1 at 5 h and fell slightly at 7 h. Immediately before the fifth dose. The areas under the plasma level-time curves (AUC) were significantly (P less than 0.001) increased by the chronic regimen, and although the individual values were highly variable, the increase in AUC from the first to the fifth dose was significantly (P less than 0.001) correlated within each subject. Ethylenediamine concentrations after a single dose reached a peak of 0.16 micrograms ml-1 at 1 h, and returned to baseline values in 5-7 h. After the fifth dose, the plasma levels and kinetics were no different from those obtained with the first dose indicating that ethylenediamine did not accumulate as a result of chronic administration of aminophylline in a form designed to give steady-state levels of theophylline.
Adult↗
Local passive immunization by monoclonal antibodies against streptococcal antigen I/II in the prevention of dental caries.
Local passive immunization with monoclonal antibodies (Mc Ab) to Streptococcus mutans was attempted as an alternative approach to active systemic immunization. We prepared an immunoglobulin G class Mc Ab to the cell surface protein determinant of streptococcal antigen I/II and applied it repeatedly to the teeth of rhesus monkeys. This resulted in decreased colonization by S. mutans in fissures and smooth surfaces of teeth and no dental caries, unlike the results in control animals, which developed caries and showed a high proportion of S. mutans on their teeth. There was no significant difference in serum, salivary, or gingival fluid antibodies to S. mutans between the two groups of animals. Any objections raised over systemic immunization inducing cross-reactive antibodies are therefore overcome by local passive immunization. The mechanism of prevention of colonization has not been established, but we postulate that the Mc Ab which is directed against an important cell surface antigenic determinant of S. mutans (streptococcal antigen I/II) prevents adherence of S. mutans to the acquired pellicle on the tooth surface. S. mutans reacts with the Mc Ab and becomes opsonized, phagocytosed, and killed by the local gingival traffic of neutrophils.
Animals↗
Increases in intrathoracic pressure do not explain the rise in left ventricular end-diastolic pressure that occurs during exercise in patients with chronic obstructive pulmonary disease.
During exercise, patients with chronic obstructive pulmonary disease (COPD) increase their pulmonary arterial wedge (Ppaw) and left ventricular (LV) end-diastolic pressures more than normal control subjects. The increase in pressure is commonly attributed to an increase in intrathoracic pressure (Pit). However, mean esophageal pressure (Pes) does not increase with supine exercise in patients with COPD. Because changes in Pes may not represent changes in Pit when recorded in the supine position, we measured Ppaw and Pes during upright exercise in 8 patients with severe air-flow limitation (mean +/- SD) FEV1, 0.88 +/- 0.27 L secondary to COPD and no history or electrocardiographic abnormalities suggesting a previous myocardial infarct, history of angina, evidence of systemic hypertension, or use of cardiac medications. In addition, all patients completed a progressive exercise test to exhaustion without angina or ST segment changes, and all had normal LV function at rest assessed by equilibrium radionuclide ventriculography. The Ppaw increased a mean of 7.2 +/- 4.3 mmHg, whereas Pes increased a mean of only 1.3 +/- 1.6 mmHg. By multiple linear regression analysis, Ppaw was significantly associated with the work level performed (p less than 0.01), but had no significant association with Pes (p greater than 0.1). The change in Ppaw could not be attributed to changes in Pes. If changes in Pes during upright exercise are representative of changes in Pit or juxtacardiac pressure, a rise in Pit does not explain the exercise-induced increase in Ppaw and LV end-diastolic pressure that occurs in patients with COPD.
Blood Gas Analysis↗
Nifedipine dilates the pulmonary vasculature without producing symptomatic systemic hypotension in upright resting and exercising patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease.
Vasodilator therapy may lower pulmonary vascular resistance in patients with chronic air-flow limitation. However, the effects of these agents on left ventricular afterload, cardiac output, and bronchial smooth muscle could lower the calculated pulmonary vascular resistance without specifically affecting pulmonary vascular tone. In addition, systemic hypotension in the upright position and worsening ventilation/perfusion heterogeneity could limit their use. We determined the pulmonary driving pressure (pulmonary arterial-pulmonary arterial wedge pressure) to flow relationship, as well as the transmural pulmonary arterial pressure in 9 patients with severe chronic air-flow limitation with pulmonary hypertension while in a clinically stable condition. Measurements were made at rest and during 3 stages of progressively increasing upright exercise on a bicycle before and after a single 20-mg dose of nifedipine. Nifedipine displaced both the driving pressure to flow and the pulmonary arterial transmural pressure to flow relationships towards higher flows in every subject, suggesting an active vasodilation. In the upright position, PaO2 did not change, and the systemic arterial pressure was only mildly reduced. In patients with pulmonary hypertension from chronic air-flow limitation, acute administration of nifedipine to upright patients causes pulmonary, as well as systemic vasodilation without causing symptomatic hypotension or reducing arterial oxygenation.
Adult↗
The helper and suppressor functions of primate T cells elicited by a 185K streptococcal antigen, as compared with the helper function elicited by a 4K streptococcal antigen.
Helper and suppressor functions of human T lymphocytes that act on antibody-forming B cells were elicited by a large 185K streptococcal cell wall antigen. However, a small 4K streptococcal peptide elicited helper but no suppressor function. These differences in the functional activities of the large and small m.w. streptococcal antigens (SA) were confirmed by direct immunisation of rhesus monkeys with the 185K-SA and 4K-SA. Sequential studies have shown that whereas the 185K-SA elicits dose-dependent helper and suppressor activities, the 4K-SA elicits only helper function. Cell-depletion studies with human cells suggest that removal of T8+ cells by killing with OK.T8 and complement leads to a loss of suppressor and a broadening in the concentration of 185K-SA, which elicits helper activity. Because the 4K-SA does not elicit suppression, removal of T8+ cells does not affect this function. However, similar depletion of T4+ cells results in loss of the helper activities, both with the 185K-SA and 4K-SA, and again a broadening in the concentration of the 185K-SA, which elicits suppression. Direct comparison by autoradiography between 125I-labeled 185K-SA and 4K-SA suggests that both antigens can bind directly to monocytes or T8+ VV+ cells. Furthermore, both antigens can induce helper function if T4+ cells are reconstituted with either monocytes or T8+ VV+ cells. Attempts will now be made to sequence the amino acid determinants of the 185K-SA, so as to define the epitopes responsible for the two major regulating functions elicited by this antigen.
Animals↗
A perspective on molecular mechanical and molecular dynamical studies involving DNA.
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Base Sequence↗
Uranus: microwave images.
Observations of Uranus at wavelengths of 2 and 6 centimeters with the Very Large Array were made in 1980 and 1981. The resulting maps of brightness temperature show a subsolar symmetry at 2 centimeters but a near-polar symmetry at 6 centimeters. The 6-centimeter maps show an increase in temperature from equator to pole with some evidence for a warm "ring" surrounding the north pole. The disk-average temperatures (147 +/- 5 K and 230 +/- 6 K at 2 and 6 centimeters, respectively) are distinctly lower than recently reported values; these results suggest that the secular increase in temperature reported during the last 15 years has been reversed. The variations in brightness temperature probably reflect variations in ammonia abundance in the planet's atmosphere, but the mechanism driving these variations is still unclear.
Ammonia↗
Sequential development of helper and suppressor functions, antibody titers and functional avidities to a streptococcal antigen in rhesus monkeys.
Sequential development of antibody titer, functional avidity, helper and suppressor activities were investigated in rhesus monkeys. These were immunized with a single dose of 0.1 microgram to 10 mg of a streptococcal protein antigen (SA) in aluminium hydroxide. The IgG antibody titers followed the classical pattern first established in mice, of high-dose and low-dose tolerance with intermediate doses of immunity. This was correlated with a similar pattern of functional avidity of IgG antibodies, as measured by a dissociation assay. Helper and suppressor functions were assayed in parallel by inducing the corresponding factors from monkey lymphocytes in Marbrook flasks and testing the factors which cross the species barrier in cooperative cultures with CBA mouse spleen B cells. A progressive modulation of helper and suppressor activities was elicited by the increasing doses of SA, during the initial 28 days after immunization. Thus, dominant suppressor with minimal helper activity, IgG antibody titer and functional avidity were elicited by 0.1 microgram SA. However, 1 or 10 micrograms SA induced dominant helper with minimal or transient suppressor activity and high IgG antibody titers and functional avidity. Somewhat intermediate responses were elicited by 100 micrograms SA, but 1 mg and especially 10 mg SA induced dominant suppressor and minimal helper activity, with low IgG antibody titers and functional avidities. When the immune response was established, about 28 days after immunization, the intermediate dose of SA elicited IgG antibodies with high titer and functional avidity, high T cell helper but low suppressor activities. In contrast, both high- and low-dose SA induced partial tolerance, with low IgG antibody titer, functional avidity and T cell helper activity. These studies suggest cyclical development of helper and suppressor functions during the 4 weeks after immunization. The emergence of a dominant helper or suppressor function is antigen dose dependent.
Animals↗
Chemical evolution on the giant planets and Titan.
We summarize the current status of atmospheric chemistry in the atmospheres of the outer solar system with special emphasis on the question of HCN formation on Jupiter, differences between polar and equatorial compositions on Jupiter, the coloration of the Great Red Spot, and the unique environment of Titan.
Ammonia↗
Metabolism of anethole. I. Pathways of metabolism in the rat and mouse.
The metabolic fate of the naturally occurring food flavouring trans-anethole has been investigated in rats and mice. A single 50-mg/kg dose of trans-[methoxy-14C]anethole was given orally to female Wistar albino rats and by ip injection to male CD-1 mice. The major routes of elimination of 14C were the urine and expired air (as 14CO2). Excretion of 14C in the faeces and as volatile compounds in the expired air was very low (total less than 2% of the dose). Urinary metabolites were separated by solvent extraction, TLC and HPLC and were characterized by MS and GC-MS directly and following methylation or trimethylsilylation, the results being compared where possible with authentic standards. Eleven 14C-containing urinary metabolites were identified in the rat and ten in the mouse. These compounds arose from side-chain oxidation, side-chain cleavage and various conjugations. The major urinary metabolites were two isomers of 1-(4'-methoxyphenyl)propane-1,2-diol, 2-hydroxy-1-methylthio-1-(4'-methoxyphenyl)propane and 4-methoxyhippuric acid, the first three all being excreted as glucuronides. In addition to these 14C-labelled metabolites, 4-hydroxypropenylbenzene, the unlabelled product of oxidative O-demethylation of trans-[14C]anethole, was excreted extensively in urine as the glucuronide.
Allylbenzene Derivatives↗
Metabolism of anethole. II. Influence of dose size on the route of metabolism of trans-anethole in the rat and mouse.
The effect of dose size on the metabolism of trans-anethole was investigated in rodents over the dose range 0.05-1500 mg/kg. trans-[methoxy-14C]Anethole was administered to female Wistar rats by gavage and to male CD-1 mice by ip injection. Urine, faeces and 14CO2 in expired air were collected and their 14C content was measured. Urinary metabolites were separated as described by Sangster et al. (Fd Chem. Toxic. 1984, 22, 695) and quantitated by radioHPLC and TLC. The major route of metabolism of trans-anethole in rodents is via oxidative O-demethylation and the importance of this route was found to decrease with increasing dose from 56 and 72% of the dose at 0.05 mg/kg to 32 and 35% of the dose at 1500 mg/kg in rats and mice, respectively. Over this dose range the elimination of 14C-labelled urinary metabolites increased significantly in both species. There was a species-specific regioselectivity in the side-chain oxidation of anethole. The rat favoured the epoxidation route, resulting in the elimination in the urine of two 1-(4'-methoxyphenyl)propane-1,2-diol isomers, elimination of which together rose from 2 to 15% of the dose over the dose range studied. In contrast the mouse favoured omega-oxidation, yielding cinnamyl compounds and 4-methoxybenzoic and 4-methoxyhippuric acids, the elimination of the latter two rising from 10 to 42% of the dose over the dose range studied. The species differences in metabolism, and the significance of the effect of increasing dose on the metabolic route are discussed with reference to the guidance these results could give in the assessment of the risk to man from dietary exposure to trans-anethole and related compounds.
Allylbenzene Derivatives↗