Fetal thermal dose considerations during the obstetrician's watch: Implications for the pediatrician's observations

There are a number of seemingly "usual" thermal episodes during pregnancy for which it is relatively easy to determine a rudimentary aspect of thermal dose; these episodes include fever, labor, labor plus epidural, and the normally-occurring 0.5 degrees C temperature elevation above maternal core temperature of the fetus during the entirety of the third trimester. Complications can involve, for instance, fever during the third trimester. We consider the thermal doses of five different but "usual" or "normal" hyperthermic episodes during human pregnancy and compare those doses with the thermal doses involved with both single and cohort exposures of pregnant guinea pigs throughout their gestational period. The end-point studied in the guinea pigs was microencephaly. In nine of the 10 comparisons (human fetal thermal dose vs. guinea pig fetal thermal dose) the human dose is substantially larger than that of the guinea pig thermal dose, which was substantially teratogenic. This situation is essentially the inverse of the type of information contained in the Physician's Desk Reference (PDR) on drugs, in which it is not unusual to discern that at high drug levels there may be teratogenic effects in laboratory animals, but such effects were not observed at "clinical" drug levels in animals or subsequent clinical trials. With hyperthermic events, however, it appears that the teratogenically-effective thermal dose levels associated with animal testing are quite low relative to those thermal doses associated with relatively "normal" obstetric observations during a pregnancy.     

Influence of small doses human interferon-alpha intranasal injection on behavior of rats of different age

Behavior of young (3-4 month old) and ageing (12-15 month old) rats was studied during chronic intranasal application of low doses (10 ME or 350 ME) of human interferon-alpha (HIA). In ageing rats HIA did not affect dynamics (days 0th, 8th and 16th) of (a) locomotive and (b) investigative activity in the "open field" test and in two-side defensive conditioning, and (c) decreased anxiety ("open field", "light-darkness" test). In young rats HIA (a) increased locomotive activity by 16th day (it decreased in control), (b) investigative activity did not change (in control it decreased by 8th day; "open field" test), (c) anxiety decreased in the "open field" and increased in "light-darkness" tests, (d) development of conditioned reflex improved (during 2nd learning session in 5 days after the first one). Thus, small doses of HIA differently affected behavior of rats depending on the age and experimental situation. However, both HIA doses changed rats' behavior in the same direction. We suggest that chronic low doses of HIA can regulate different aspects of behavior, but not suppress activity as it is commonly thought. This regulation can be performed via modulation of neuro-immuno-endocrine complex.     

Behaviour in aggregates of irradiated imaginal disk cells ofDrosophila

Summary The ability of dissociated cells to reaggregate, grow in culture (in vivo) and differentiate cuticular structures following increasing doses of X-ray radiation has been studied.At low doses (up to 5 Kr) reaggregation, but not cell viability, is affected. The reaggregation ability of irradiated cells is improved with increasing time between irradiation and aggregation and can be rescued by mixing irradiated and non-irradiated cells.On the contrary, growth and cell differentiation seem to be cell autonomous events. At doses between 5 Kr and 8 Kr cell proliferation is impaired, and after doses over 10 Kr reaggregates show a negative growth. The differentiation of cuticular structures, such as chaetes and trichomes, show a different X-ray sensitivity.A unifying interpretation of these results is outlined in the discussion.We want to thank Miss P. Garrido for her skill technical assistence. Mr. P. Santamaria's and Mr. P. Ripoll's discussions are thankfully acknowledged.     

Caffeine-phenylethylamine combinations mimic the amphetamine discriminative cue

Although caffeine-phenylethylamine combinations are widely available as over-the-counter medications or as "legal" stimulants, little information is available concerning their behavioral pharmacology or abuse potential. In the present study, rats were trained in a food-reward, two-lever operant drug discrimination paradigm to differentially respond after saline or 0.5 mg/kg amphetamine injections. Tests for generalization to the amphetamine cue indicated only modest amphetamine-lever responding at various doses of caffeine alone or at various doses of ephedrine/phenylpropanolamine (PPA) combinations, but complete generalization to the training cue was found with higher doses of the triple combination (caffeine, ephedrine, and PPA) or with caffeine-ephedrine or caffeine-PPA combinations. All drugs produced response rate decreases at higher doses. These data clearly indicate that certain "legal" stimulants mimic the amphetamine cue and suggest that caffeine may interact additively with phenylethylamines to produce the cue.     

Effect of clomiphene citrate on the rabbit ovary

Summary The effect of clomiphene citrate on the rabbit ovary was studied in mature nulliparous rabbits pretreated with three consecutive doses ranging from 0.01–10.0 mg/kg per day. With increasing doses a trend of decrease in mean ovarian weight (mg/kg body weight) is observed 2 days after termination of treatment. Five days later a significant increase occurs, which then subsides again to control values on day 12 after termination of treatment. During this period, no matings or injections of luteinizing hormone were performed to trigger ovulation; consequently no ovulations are observed. Folliculogenesis appears as normally; number and morphology of follicles are within normal ranges. No endogenous, spontaneous gonadotropin surges are detected in blood serum up to the 7th day after termination of treatment (2 and 10 mg doses). The surface epithelium of the ovary resembles normal germinal epithelium; however, after treatment with high doses a secretory-like activity is observed, accompanied with ultrastructural changes.Supported by the Deutsche Forschungsgemeinschaft, Special Program on Biology and Clinics of Reproduction. (Grant Be 524/7-7).Visiting Scientist from the Department of Obstetrics and Gynecology, Hadassah University Hospital, Jerusalem, Israel.     

Effects of radiation on normal tissues: Hypothetical mechanisms and limitations of in situ assays of clonogenicity

Summary It is argued that proliferating normal tissues fall into two categories. In type H (for hierarchical) tissues, cells either multiply or perform tissue-specific functions. Sterilizing doses of radiation immediately initiate a gradual depopulation of irreversibly postmitotic, mature cells. The constant rate of functional cell depletion is given by physiological longevity of the cells. Consequently the onset of maximal depopulation is dose-independent and, after a range of radiation doses, the peak of milder damage is seen earlier than that of a more severe one. In type F (for flexible) tissues all cells are assumed to have the potential for proliferation and are also engaged in tissue-specific functions. Radiation leads to dose-dependent loss of the functional cells through their mitotic death, both immediately after exposure and during the next phase of increased compensatory proliferation resulting in accelerated expression of radiation damage (avalanche). Consequently the more severe damage following larger doses of radiation is seen earlier than the milder one produced with smaller doses.Assays of cell clonogenicity in vivo concern almost exclusively type H populations. The large radiation/drug/heat doses administered in these assays serve both to dilute the clonogenic cells by at least two orders of magnitude, and to produce a measurable response. When comparing two agents or interpreting their combined action it is advisable to ensure that the dilution step yields qualitatively comparable samples of clonogenic cells to be then characterized in terms of dose-survival curve parameters.Read at the Fifteenth Annual Meeting of the European Society for Radiation Biology (Rotterdam, 25th–29th August, 1980)     

Psychotropic effects of glutamic acid diethyl ester in mice

In 1 hour after intraperitoneal injection glutamic acid diethyl ester (GED) in doses 200 and 500 mg/kg decreased locomotor activity and exploratory patterns of mice in "open field" test. GED in doses 100 and 200 mg/kg diminished the immobilization period of animals in forced swimming test, that proves the reversal interaction of glutamatergic and catecholaminergic systems in CNS. Glutamate receptors antagonist--GED in doses 100-200 mg/kg disrupted passive avoidance reaction at 30 min before acquisition and retrieval, therefore glutamate receptors are involved into fixation and retrieval of memory engram.     

The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: study of errors in dosimetry

To provide direct estimates of cancer risk after low-dose protracted exposure to ionizing radiation, a large-scale epidemiological study of nuclear industry workers was conducted in 15 countries. As part of this study, identification and quantification of errors in historical recorded doses was conducted based on a review of dosimetric practices and technologies in participating facilities. The main sources of errors on doses from "high-energy" photons (100-3000 keV) were identified as the response of dosimeters in workplace exposure conditions and historical calibration practices. Errors related to dosimetry technology and radiation fields were quantified to derive period- and facility-specific estimates of bias and uncertainties in recorded doses. This was based on (1) an evaluation of predominant workplace radiation from measurement studies and dosimetry expert assessment and (2) an estimation of the energy and geometry response of dosimeters used historically in study facilities. Coefficients were derived to convert recorded doses to H(p) (10) and organ dose, taking into account different aspects of the calibration procedures. A parametric, lognormal error structure model was developed to describe errors in doses as a function of facility and time period. Doses from other radiation types, particularly neutrons and radionuclide intake, could not be adequately reconstructed in the framework of the 15-Country Study. Workers with substantial doses from these radiation types were therefore identified and excluded from analyses. Doses from "lower-energy" photons (<100 keV) and from "higher-energy" photons (>3 MeV) were estimated to be small.     

Chemical sympathectomy induced by 5.6-dihydroxytryptamine

Summary The effect of different doses of 5.6-dihydroxytryptamine—a serotonin analogue which produces a degeneration of serotonin containing nerve terminals in the rat brain—on the noradrenaline (NA) content and—storage sites of peripheral sympathetic nerves in the mouse and rat heart, spleen, rectum and vas deferens has been investigated by fluorescence—, electron microscopical and chemical methods. Moderate doses of 5.6-dihydroxytryptamine (5.6-DHT) (10–45 mg/kg ip.) cause a temporary, reversible displacement of noradrenaline from the adrenergic nerves concomitant with a significant increase in the number and opacity of small and especially large granular vesicles. The recovery of the neuronal NA concentration is, however, retarded after doses higher than 45 mg/kg (60 or 100 mg/kg ip.); a partial degeneration of varicose NA terminals is verified fluorescence- and electron microscopically. A combined treatment of animals with tyrosine hydroxylase inhibitors (-methyl-paratyrosine or -propyl-dopacetamide) and 5.6-DHT, in some instances also followed by reserpine, potentiates the destructive properties of 5.6-DHT; a similar potentiation is accomplished by reserpine posttreatment or by an additional pretreatment of animals with reserpine and nialamide.The results suggest that 5.6-DHT when given in moderate doses (up to 45 mg/kg) may be handled by sympathetic adrenergic nerves like a false neurotransmitter which displaces noradrenaline from the stores, but that it causes a chemical degeneration of noradrenaline containing nerve terminals when applied either in single high doses (60 or 100 mg/kg ip.), or when administered in moderate non-degenerative doses together with drugs that impair the neuronal inactivation mechanisms for 5.6-DHT (granular uptake and storage mechanism and/or monoamine oxidase activity) and thus provoke a temporary increase in the amount of free 5.6-DHT in the neuron's cytoplasm.The molar efficiency of 5.6-DHT in causing a chemical sympathectomy is clearly inferior to that caused by 6-hydroxydopamine. The differences are probably mainly due to differences in the affinity of both drugs to the amine uptake system located at the cell membrane and the membrane of the intraneuronal storage vesicles of the adrenergic nerve terminals.Supported by grants from the Deutsche Forschungsgemeinschaft.     

Pharmacokinetic monitoring of aminoglycoside therapy: an optimal method of administration of individualized doses of gentamicin and sisomicin]

One of the most promising approaches to design the optimal schedule for TDM provides a single determination of a drug content in the blood specimen being collected at the "ideal" sampling time equaled to the inverse value of the elimination rate constant. Three versions of the one-point method when the specimen was collected at the "ideal" time point (3 h after a single i.m. drug administration), as well as at the times of "maximum" (1 h after injection) and "minimum" (6 h after injection) concentrations were compared by the retrospective analysis of the routine TDM data obtained with HPLC-techniques in 47 patients treated with gentamicin or sisomicin. As optimal individualized doses were considered ones calculated on the base of three subsequent determinations of the aminoglycoside concentrations, i.e. 1, 3 and 6 h after injection, and the estimation of individual clearance values (Cli). The optimal doses (DCl) were calculated according to equation DCl = Dp.Cli/Clp, where Dp and Clp are population values of the dose (1 mg/kg) and Cl 72.4 ml/(h.kg), respectively. The approximate values of the individual doses (D) were calculated according to equation D = Dp.Cp/Ci, where Ci is the individual drug serum concentration 1, 3 or 6 h after administration and Cp is the corresponded population value (4.8, 1.9 and 0.8 mg/l, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

The Peripheral Versus Central Antinociception of a Novel Opioid Agonist: Acute Inflammatory Pain in Rats

Opioid analgesics devoid of central side effects are unmet medical need in the treatment of acute pain (e.g. post-operative pain). Recently, we have reported on 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU), a novel opioid agonist of high efficacy producing peripheral antinociception in subchronic inflammatory pain in certain doses. The present study focused on the antinociceptive effect of 14-O-MeM6SU compared to morphine in formalin test of an early/acute (Phase I) and late/tonic (Phase II) pain phases. Subcutaneous 14-O-MeM6SU (253–1012 nmol/kg) and morphine (3884–31075 nmol/kg) dose dependently reduced the pain behaviors of both phases. Co-administered naloxone methiodide (NAL-M), a peripherally acting opioid antagonist, abolished the antinociceptive effect of 506 nmol/kg 14-O-MeM6SU. On the other hand, the effects of 14-O-MeM6SU (1012 nmol/kg) and morphine (15538 nmol/kg) were only partially affected by NAL-M, indicating the contribution of CNS to antinociception. Locally injected test compounds into formalin treated paws caused antinociception in both phases. Locally effective doses of test compounds were also injected into contralateral paws. Morphine showed effects in both phases, 14-O-MeM6SU in certain doses failed to produce antinociception in either phase. A NAL-M reversible systemic dose of 14-O-MeM6SU and the lowest systemic effective dose of morphine were evaluated for their sedative effects following isoflurane-induced sleeping (righting reflex). In contrast to morphine, 14-O-MeM6SU in certain antinociceptive doses showed no impact on sleeping time. These data highlight that high efficacy opioids of limited CNS penetration in certain doses mitigate somatic and inflammatory pain by targeting MOR at the periphery.     

Effector modeling of the action of GABA-receptor complex ligands. Functional interactions of subunits of the complex

The distribution of the minimum effective doses of bicuculline, corasole and picrotoxin was studied in intact mice and in mice administered different doses of 1.4-benzodiazepines (phenazepam and its 1,2,4,5-tetrahydroxy derivatives) and sodium barbital. The changes in the "dose-response" relationship for thiosemicarbazide have been observed with the administration of the increasing doses of phenazepam and sodium barbital. The effects registered correspond to the modifications of the GABA-receptor complex by exogenous ligands. The forms of the "dose-response" relationship observed, the types of the antagonism between pharmacological agents and the cooperation of their interaction correspond to the indices obtained from the "quartet" model of the receptor-channel complex.     

The absence of the facts connected with the genomic instability after the irradiation in low doses by radiation with low LET

In the review which is a brief account of more complete document (Koterov A.N. // Int. J. Low Radiat. 2005. V. 1. No. 4. P. 376-451) the data of world researches devoted to a phenomenon of radiation-induced genomic instability (RIGI) are considered. The purpose of the review is the definition of the bottom limit of radiation doses which induced of RIGI in experiments at different methodical approaches (irradiation in vitro, in vivo, in utero, bystander effect and transgeneration effects of radiation). The action only radiation with low LET is examined. Among several hundreds works wasn't revealed any fact, when RIGI induced by low doses irradiation (up to 0.2 Gy) for normal cells and for organism left from maternal womb. Six exceptions are revealed which are named as "apparent" so in all cases the abnormal, unstable, defective objects or ambiguous final parameter were used. Thus, RIGI at low doses of radiation with low LET is a myth.     

Radiation-induced bystander effects and adaptive responses--the Yin and Yang of low dose radiobiology?

Our current knowledge of the mechanisms underlying the induction of bystander effects by low doses of high or low LET ionizing radiation is reviewed. The question of what actually constitutes a protective effect is discussed in the context of adaptive (often referred to as hormetic or protective) responses. Finally the review considers critically, how bystander effects may be related to observed adaptive responses or other seemingly protective effects of low doses exposures. Bystander effects induce responses at the tissue level, which are similar to generalized stress responses. Most of the work involving low LET radiation exposure discussed in the existing literature measures a death response. Since many cell populations carry damaged cells without being exposed to radiation (so-called "background damage"), it is possible that low doses exposures cause removal of cells carrying potentially problematic lesions, prior to exposure to radiation. This mechanism could lead to the production of "U-shaped" or hormetic dose-response curves. The level of adverse, adaptive or apparently beneficial response will be related to the background damage carried by the original cell population, the level of organization at which damage or harm are scored and the precise definition of "harm". This model may be important when attempting to predict the consequences of mixed exposures involving low doses of radiation and other environmental stressors.     

Modification by cis-diamminedichloroplatinum (II) of the radiation dose-response curve for intestinal crypt cells in mice

The effect of cis-diamminedichloroplatinum (II) (c-DDP) on the shape of the radiation dose-response curve for mouse duodenal crypt cells was investigated. A priming X-ray dose was followed 18 h later by graded test doses (single doses or five equal fractions at 3-h intervals) with or without c-DDP. Curves were fitted by a linear quadratic (LQ) relationship. The drug modified the dose-response curve by enhancing both the alpha and the beta terms. Repair kinetics were analyzed in split-dose experiments. c-DDP caused a minor, nonsignificant decrease in the rate of repair after irradiation. The survival ratio after split-dose irradiation, when the same X-ray doses were given, was actually slightly increased by the drug. This paradoxical effect can be explained by the fact that c-DDP mainly increased the beta term in the LQ relationship. There was no significant increase in crypt cell survival when split-drug doses were given alone at increasing intervals, suggesting no cellular repair after c-DDP treatment. The data are discussed in the light of the recently proposed "lethal and potentially lethal" (LPL) unified repair model of Curtis.     

Do benzodiazepine receptors mediate the anticonflict action of pentobarbital?

The effects of the benzodiazepine antagonist CGS 8216 (2-phenylpyrazolo[4,3-c]quinoline-3(5H)-one) were examined in a thirsty rat conflict test in the presence and absence of pentobarbital. CGS 8216 (2.5-10 mg/kg i.p.) did not affect nonpunished responding, but doses of 5 and 10 mg/kg significantly reduced the rate of punished responding (i.e., the number of 3 second drinking episodes in a "shock" contingency). However, a dose of CGS 8216 which did not significantly alter punished responding (2.5 mg/kg) antagonized the anticonflict actions of pentobarbital. These observations suggest that while high doses of CGS 8216 may elicit an "anxiogenic" response in rodents, lower doses of CGS 8216 antagonize the anticonflict actions of a compound which has been shown to enhance benzodiazepine affinity in vitro. These data imply that the anticonflict actions of pentobarbital may be mediated through benzodiazepine receptors.     

The effectiveness of short-term versus long-term exposures to Photofrin II in killing light-activated tumor cells.

Asynchronous populations of mouse EMT-6 tumor cells were exposed to various doses of 630-nm light in slowly stirred aerobic suspensions after both short-term and long-term exposures to Photofrin II. All survival curves are characterized by a "threshold" light dose below which no cell inactivation occurs followed by a steep light-dose response. Both the shoulder widths and the inactivation curve slopes are functions of Photofrin II concentration. After high doses of light where survival levels are 0.003 and lower, "resistant tails" are observed on some survival curves. Light doses required to inactivate 50% of tumor cell populations were obtained from whole survival curves and their reciprocals (1/D50% survival) used as inactivation "rates". The amount of Photofrin II within cells was measured by a fluorescence assay. Per unit of fluorescence, this photosensitizer is at least 10 times more effective after long-term than after short-term exposures. After long-term exposures, both fluorescence activity and photosensitizing effectiveness are retained in washed cells for several hours. After short-term exposures, a majority of both the fluorescence and photosensitizing activity is lost by multiple washings or stirring in tissue culture medium without drug. These data suggest that the cellular compartments associated with photosensitization after short-term exposures to Photofrin II are probably different from the cellular compartments associated with photosensitization after long-term exposures to the drug. The data are consistent with known properties of the monomeric and oligomeric components of Photofrin II.     

New analytical methods for genetic dissection of biological responses to DNA lesions

Two proteins that process damaged DNA may function in the same pathway, or in redundant ("synergistic") pathways that respond to the same lesion(s), or in parallel pathways targeted to different lesions. Previously, extended plots of positive outcomes (such as cell survival) or negative outcomes (such as reduced tissue growth) vs. genotoxic dose yielded empirical estimates of wt and mutant resistances to DNA damage. Recently, wt and mutant outcomes have been compared at one or two doses. The criterion for parallel pathways was "additivity": wt positive outcomes roughly equal to numerical sums of single-mutant positive outcomes or double-mutant negative outcomes equal to sums of single-mutant negative outcomes. For redundant pathways, wt positive outcomes or double-mutant negative outcomes were postulated to be "greater-than-additive" relative to single-mutant sums. Equations derived here to describe parallel and redundant pathways provide no rigorous theoretical justification for these criteria. Furthermore, simulations using these equations generate additive or greater-than-additive outcomes for both parallel and redundant pathways, depending on the values chosen for various parameters. Proposed new methods to compare wt vs. mutant plots of negative outcomes against doses of genotoxic agents yield three different but complementary estimates of resistances to DNA damage: respective plot slopes where mutant and wt outcomes are the same (inversely proportional to instantaneous damage-resistance strengths), respective total doses that cause the same outcomes (total resistance capacities), and respective dose thresholds where negative outcomes are first detected. Analyses of experimental examples suggest that greater-than additive threshold doses provide the most straightforward criteria for pathway redundancy.