Single-dose Experiments Research Articles

Human plasma levels of some anti-migraine drugs.

SYNOPSISFour compounds of therapeutic value in the treatment of migraine attacks or for the prophylaxis of migraine and other vascular headaches, ergotamine, dihydroergotamine, methysergide and pizotifen are given in low dosages and achieve low in vivo concentration. Human plasma levels were determined by measurement of radioactivity after oral administration of the corresponding radioactively labeled compounds. The labeling of the four compounds with tritium or carbon‐14 is briefly described. The procedure to measure radioactivity of the blood samples is given. The values from single dose experiments in healthy volunteers were analysed based on a compartment model which allows for the formation of metabolites. The calculated pharmacokinetic constants have been used for simulations and predictions of plasma levels after different therapeutic dosages.

Survival of mouse L-929 cells following neutron irradiation.

Mouse L-929 cells were exposed in a monolayer to x rays and to a 3.5 MeV neutron beam for comparison of damage effects. Single dose experiments showed a radiobiological effectiveness of 1.5 for neutrons when compared to x rays. Both single and paired dose experiments indicated that the cells were unable to repair neutron-induced damage. Dinitrophenol was found to increase the survival of those cells irradiated with neutrons.

Enhancement of hepatic and renal tumorigenesis with thyroidectomized NZR/Gd rats treated with dimethylnitrosamine.

Endocrine modulation of DMN carcinogenesis was studied in NZR/Gd rats preconditioned by starving 48 hr and then injected i.p. once with 20 mg DMN/kg. Intact rats developed kidney tumors (44% TBA), most of tubular epithelial type resembling human tumors rather than mesenchymal. Thyroidectomy (Tx) 45 days before DMN significantly enhanced DMN carcinogenesis, renal carcinoma incidence increasing to 69%. Renal carcinomas showed more signs of malignancy in Tx rats. Other neoplastic responses useful for further studies including tumors in nasal epithelium (13%), liver (18%, increased to 59% in Tx rats), and lung (40%): these tumors were rare or not previously reported in single-dose experiments in other rat strains. A sex difference in lung tumor incidence (male 70%, female 16%) was statistically significant and thyroidectomy reduced the sex-differential (to 54% and 39% respectively). The increased incidence of kidney and liver tumors could be due to altered metabolism of DMN in tissues of Tx rats.

51Cr-EDTA, 91Y and 141Ce as Nonabsorbed Reference Substances in the Gastrointestinal Tract of the Chicken

The use of 91Y, 51Cr-EDTA, and 141Cr as nonabosrbed reference substances in the gastrointestinal tract of the chick was examined. In single oral dose experiments, more than 95% of the isotopes administered was recovered from the gastrointestinal tract 3 hours after dosing. 51Cr was higher in blood than the other isotopes tested. When the isotopes were fed continuously, the ratio of 91Y to 141Cr changed little throughout the gastrointestinal tract. However, the ratio of 91Y to 51Cr was higher in the crop and gizzard and lower in the duodenum than in the feed. Thus, passage time was shorter for 51Cr in the crop and gizzard and longer in the duodenum than that of 91Y. On the basis of distribution between solid and liquid phases in the intestinal contents, 91Y or 141Ce appears to be a suitable reference substance for studying the absorption of nitrogen and fatty acids, wheras 51Cr-EDTA would be preferable for bile acid absorption studies.

Cumulative excretion of succinonitrile in mice

Mice were given [ 14C]succinonitrile intraperitoneally at a dose of 0.5 mg (1 μCi) per 20 g in single and multiple dose experiments. Cumulative excretion of total 14C, and of four radioactivity fractions, two of which contained unchanged succinonitrile, and cyanide excreted as thiocyanate, were recorded. Unmetabolized succinonitrile was virtually absent after 24 hr, but metabolites persisted longer. Evidence for accumulation of cyanide was obtained. The possible nature of unidentified metabolites was considered.

Repeated administration of 35S-methimazole: pattern of accumulation and oxidation by the rat thyroid.

Repeated administration (every 8 hr) of 35S-methimazole to rats resulted in gradual accumulation of 35S-radioactivity by the thyroid gland until the 7th or 8th dose was given. Following this a plateau-level was attained. Chromatographic analysis showed that the metabolite sulphate accumulated in a pattern similar to the 35S total activity, whereas intact methimazole increased until the 3rd dose was given and, subsequently a plateau level in the thyroid was achieved: the level of this plateau was found to be proportional to dose with the two dose levels used (50 µg and 100 µg). The ratio sulphate/unmetabolised methimazole varied throughout the experiment and seemed to be inversely proportional to dose. The plasma 35S radioactivity reached a plateau level in the case of the 50 fig dose and continued to increase throughout the study in the case of the 100 µig dose. A single dose experiment showed that the uptake and intrathyroid metabolism of 35S-methimazole is affected by iodine intake and route of administ...

Sodium versus Meglumine Diatrizoate in Excretory Urography

In anesthetized dogs the i.v. injection of mannitol, sodium diatrizoate, meglumine diatrizoate or meglumine hydrochloride produced diuresis approaching a steady-state. During this period the apparent volumes of distribution of meglumine and diatrizoate were similar and greater than that of inulin; the plasma concentration, renal clearance, and rate of urinary excretion were the same for meglumine and diatrizoate; their renal clearance was identical with that of inulin. Excretion of urine and urinary electrolytes was greater after meglumine diatrizoate than after sodium diatrizoate or meglumine hydrochloride. Urinary concentration of diatrizoate was greater after sodium than after meglumine diatrizoate; the relative radiopacities should be as 11/9. This difference is believed to result from the influence of the two impermeant ions on the excretion of other ions on a statistical basis. Single-dose experiments revealed no such difference between sodium and meglumine diatrizoates due to errors arising from collection of urine from the bladder.

Plasma concentrations and effects of methaqualone after single and multiple oral doses in man.

Three healthy subjects took methaqualone (1.0 mg/kg) once daily for 16 days. Equilibrium concentrations in plasma were established after multiple oral doses and there was a linear post-steady state decline in the log plasma concentration of methaqualone. The drug was also given as single oral doses and plasma concentrations were followed for 5 days (t1/2=36 to 38 h.). Sedative effects were studied by psychophysiological tests and subjective ratings both in the single and multiple dose experiments. A significant impairment of flicker fusion discrimination ability occurred during the increase in the plasma concentration of the drug; maximum effects preceded peak plasma concentrations and the impairment disappeared whilst plasma concentrations were still high. The same effects were found in the subjective ratings. The drug was shown to have a possible tremorogenic effect after a hypnotic dose. One subject experienced sedation during the multiple dose experiment, despite the use of a low dose, an observation that should be taken into account, e.g. in car driving.

The fate of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) following oral administration to man

Five human male volunteers ingested a single dose of 5 mg/kg without incurring detectable clinical effects. Concentrations of 2,4,5-T in plasma and its excretion were measured at intervals after ingestion. The clearances of 2,4,5-T from the plasma as well as its excretion from the body occurred via apparent first-order rate processes with half-lives of 23.10 and 23.06 hr, respectively. Essentially all of the 2,4,5-T was absorbed into the body and excreted unchanged in the urine. In the body, 65% of the 2,4,5-T resided in the plasma where 98.7% was bound reversibly to protein. The volume of distribution was 0.079 liters/kg. Utilizing the kinetic constants from the single dose experiment, the expected concentrations of 2,4,5-T in the plasma of individuals receiving repeated daily doses of 2,4,5-T were calculated. From these calculations, it was determined that the plasma concentrations would essentially reach a plateau after 3 days. If the daily dose ingested in mg/kg is A 0, the concentration in the plasma after attaining plateau would range from 12.7 A 0 to 22.5 A 0 μg/ml. This range would converge to approximately 17 A 0 μg/ml as the daily dose A 0 is distributed throughout the day.

Renal lithium excretion in man

Renal lithium excretion in man

Accumulation of Chromosome Damage under Continuous Low Dose Rate Exposure

Various renewal tissues of the body can maintain function and a steady level of cell population for relatively long periods under high dose rates of continuous irradiation, apparently indicating no serious accumulation of damage affecting cell proliferation. The epithelium of the small intestine can maintain function and a steady cell population at dose rates as high as 400 rads/day, the bone marrow only at doses of 50 rads/day or less, while collapse with progressive cellular depopulation will occur in the testis after a few rads per day (14). In rapidly dividing renewal systems, there is an effective selection-out of damaged cells as well as repair of sublethal damage affecting proliferation. In a more slowly dividing system, such as the liver, there is also apparently some repair or elimination of radiation damage. The pattern of cell proliferation after partial hepatectomy is relatively little disturbed by prior exposure to dose rates of from 16 to 70 rads/day, in spite of the accumulation of large radiation doses and in the presence of considerable chromosome injury. There is a delay in onset of DNA synthesis and cell division in the parenchymal cell population which appears to be dependent on the dose rate, the duration of exposure, and the accumulated dose. At higher dose rates and after long periods of irradiation, there is (a) a decrease in the rate of entry of cells into synthesis and mitosis; (b) a decrease in the number of cells taking part in the regenerative process; (c) an increase in the overall duration of cell proliferation during regeneration, and (d) an increase in the number of observable chromosome aberrations and possibly of polyploid parenchymal cells (9–11). A radiation effect in the nonproliferating liver that becomes manifest only upon proliferation is the production of chromosome aberrations (1, 2, 5, 6, 16, 17, 20, 21, 24, 26). Following CCl4-induced liver regeneration in rats, the yield of spontaneous aberrations increases with age and the number of radiation-induced chromosome injuries decreases with time. These effects are observed two hundred and fifty days after a single exposure or after multiple hepatectomies. The decrease is less marked than the proliferative inhibition, however, and the rate of reduction is greater than could be explained by the elimination of injured chromosomes at cell division (1, 2, 7, 16, 24). After continuous exposure, the frequency increases faster than in unirradiated controls, but not as fast as would be predicted from single-dose experiments (5, 7, 21, 22). The accumulation of chromosomal or other nonlethal cellular damage under continuous irradiation in the stem-cell compartment of slowly proliferating tissues is one of the major factors which might affect the regenerative capacity of the precursor cell population and its ability to deal with chronic stress.

The dose-response relationship for epithelial cells of skin.

Atechnic has been developed for cloning epithelial cells of mouse skin. This method makes it possible to establish dose-survival curves for these cells and, in addition, to study the kinetics of recovery at the cellular level in skin. All experiments were performed in situ on the mouse back to simulate the situation obtaining in radiotherapy. If single surviving epithelial cells will regrow, and the results of these experiments suggest that they will, then it is possible to take a known initial population of cells, expose them to a known dose of radiation, D, and count the survivors. The numbers of survivors may then be expressed as a fraction of the initial population, as with in vitro cell-plating experiments. The initial population of epithelial cells is isolated from surrounding skin by an annulus of lethally irradiated cells, and this isolated area then exposed to the experimental dose D. If D is large enough, all the epithelial cells will be sterilized and complete ulceration will follow. If one or more cells survive, then a nodule of skin will regrow, becoming visible in about fourteen days. This cloning technic has the disadvantage that, because all the cells are left in situ throughout, the plating area is the same as the initial area, and, since this area is small, distinguishing one regrowing clone from another is usually impossible because of confluence before they are visible. The dose D must, therefore, be great enough to produce 0 survivors (i.e., complete ulceration) in a proportion of cases, so that the nodules observed in the remaining proportion are formed from a Poisson distribution of 1, 2, 3 etc. cells. By scoring the proportion with 0 surviving cells, the numbers of survivors may be calculated from the Poisson formula and expressed as a fraction of the initial population. By making these observations at 2 to 4 levels of survival for a constant initial population and then expanding the initial population over a thousandfold range, a dose survival curve covering several decades may be established. By using 29 kVp x rays in doses from 900 to 2,300 rads, a survival curve with a value of D0 = 135 rads was obtained. The technic is not suitable for establishing the extrapolation number from single dose experiments because the number of cells per unit area, and therefore the origin of the survival curve, cannot be accurately determined. Furthermore, the initial part of the curve (i.e. at doses less than 900 rads) cannot be defined by experimental points because of the difficulty in isolating small numbers of cells as the initial population.

Pathology of Multiple Intravenous Doses of Polonium

The author has reviewed the literature on the pathology and hematology of single intravenous or oral doses of polonium-210 in other papers of the Supplement (1-3). The literature cited at this point in the present paper is concerned with effects of multiple intravenous doses of polonium-210. Data on the distribution and excretion of polonium and on the mortality, life span, and growth of rats in the present study have been reported by Stannard et al. in other papers of this Supplement (4,5). Spoerl and Anthony (6) have summarized the effects of multiple intravenous injections of polonium-210 observed in experiments performed at Mound Laboratory. These included an experiment in which rats were injected with polonium at a dosage level of 2 ,uc/kg of body weight every 2 weeks for a total of ten injections, and an experiment in which rats were injected throughout life at 28-day intervals with doses of polonium (averaging 0.006 ,c/kg/mo) calculated to maintain an average body burden of 0.01 A,c/kg of body weight. The rats in the latter low-doselevel experiment were indistinguishable from their control rats in all examinations for histopathological changes. In comparison of rats injected with 2 auc/kg every 2 weeks with rats receiving single injections of doses of similar total magnitude, it was observed that the pathologic changes appeared earlier and were more marked in the multiple-dose animals, and also involved marked damage of the liver, which was not markedly affected in single-dose experiments. The present experiment on rats was performed to study effects of maintained body burdens of polonium-210 over a dosage or body burden range between a level expected, on the basis of previous experience, to cause little or no effect and a level expected to cause marked damage.

Course of transformation of benzaldehyde bySaccharomyces cerevisiae

The course of fermentation of benzaldehyde bySaccharomyces cerevisiae simultaneously fermenting a sugar substrate was studied by a polarographic method and gas chromatography. In single-dose experiments, 0.2% benzaldehyde was fermented. It was fermented within 90–120 minutes, giving rise to 23.1 to 39.2% phenylacetyl-carbinol and 40.5 to 24% benzyl alcohol. The addition of acetaldehyde to the fermentation medium retarded the transformation of benzaldehyde, lowered the formation of benzyl alcohol and raised the yield of phenyl-acetylcarbinol. In four-dose experiments the utilization of the individual doses of benzaldehyde for the formation of phenyl-acetylcarbinol is described.

Movement of Strontium in the Human Body

The replacement of body strontium was investigated in single-dose experiments by injecting Sr85 (0.5 mu C), a gamma emitter, intravenously into 2 normal subjects and following its loss from plasma for 2 days, its excretion for 4 months, and, with a whole-body counter, its retention for 1 year. Retention was not expressed as a simple exponential function but presumably the sum of many. After a few weeks it could be expressed as a power-function. From the loss of Sr85 from plasma in the first week it was possible to deduce an exchangeable pool of about 2.75 mg of Sr and clearance into bone of 0.4 mg/day. However, the 0.4 mg/ day value was not used to calculate turnover, because while the calculation is valid for exchange mechanisms it may not be applicable to osteogenesis. About 85% of the injected isotope was excreted within the year; the remaining 15% was retained in definitive, as distinct from temporary, bone. Normally about 20% of dietary Sr (about 2 mg/day in the United Kingdom) is absorbed. Therefore replacement of Sr in bone is about 0.2 x 2 x 365 x 0.15 = 22mg/ yr. In daily-dose experiments, 3 human subjects ingested 0.5 mu Cmore » of Sr85 daily for a month. Equilibrium was established within a week, when plasma levels were constant: 3, 7, and 3 m mu C/l, respectively; and daily urine excretions were constant: 25, 60, and 50 m mu C/day, so that renal clearances from plasma were approximately: 8, 8, 17 l/day. Balances in the second to fourth weekiy periods indicated a final retention of approximates 6% of ingested isotope. Estimates of the annual rate of replacement in the adult are only a few per cent per year, when calculated from long-term ingestion of Sr90, somewhat more according to short-term experiments involving ingestion of Sr/sup 85/ for a month, and much less than the total turnover of bone mineral.« less

Comparison of predicted and measured equilibrium levels for chronically administered Cs137.

The biological retention of a single oral dose of Cs/sup 137/ was obtained by whole-body counting twelve 89-day-old female RF mice for 32 days. An IBM 704 computer curvefitttng procedure was then used to reduce the retention data into three exponential components, and the resultant retention function was integrated from t/sub o/ to t/sub n/to predict the Cs/sup 137/ retention by mice of the same age at any time t/sub n/ during a chronic exposure. Both the predicted build-up of body Cs/sup 137/ activity and the equilibrium level agreed reasonably well with measured values obtained by whole-body counting 89-day-old animals whose drinking water contained 0.012 mu c Cs/sup 137/ml for a 107-day period. The urinaryto-fecal excretion ratio during the period of observed equilibrium was about 9. These findings provide addittonal experimental verification for the current practice of using retention parameters obtained from acute experiments to predict equilibrium levels which would be attained during chronic exposure conditions. Retention of Cs/sup 137/ after the termination of chronic exposure did not agree with the retention pattern predicted from the original single-dose experiment, but did agree with the retention pattern predicted from a second single-dose experiment in which animals of the same age asmore » those at the termination of the chronic ingestion period were used. The rather obscure relation between age and retention, and consequently between age and equilibrium level or radiation dose, is discussed. (auth)« less

Fission products and the dairy cow IV. The metabolism of 131I following single and multiple doses

1. The change in concentration of 131I with time in plasma, urine, milk and the thyroid gland has been followed in four cows after administration of either a single oral dose or of 131I from a decaying source every 6 hr. for 14 days.2. The observed changes in concentration following multiple doses have been compared with those predicted from the single-dose experiments.3. Small discrepancies were observed between the observed and predicted course of events in urine, milk and the thyroid gland: their significance is considered to be doubtful.