Hydrocortisone and dexamethasone in very deformable drug carriers have increased biological potency, prolonged effect, and reduced therapeutic dosage

We characterised biological properties of novel formulations of two low-potency glucocorticosteroids, dexamethasone and hydrocortisone, which have an equivalent dose ratio of 1:50 in vasoconstriction tests. The rate of such carrier-mediated, mainly non-diffusive glucocorticosteroids transport with very deformable lipid vesicles (Transfersomes) through the skin, and the corresponding cutaneous drug biodistribution data, were complemented with the drug bio-efficacy studies. The minimum effective drug dose that reduces arachidonic acid-induced murine ear oedema by 50% was used as one bioactivity indicator. The minimum drug amount ensuring such an effect in mouse skin decreases appreciably when a corticosteroid is applied epicutaneously with very deformable vesicles rather than a lotion or a crème. Specifically, the minimum effective dose for hydrocortisone in very deformable carriers is 2-3 microg cm(-2) whereas for the crème- or lotion-like preparations at least 10 microg cm(-2) is required. Such three- to fivefold relative increase of hydrocortisone potency is accompanied by at least 13%, and more often >20%, absolute drug potency enhancement. The delivery of hydrocortisone with very deformable carriers moreover prolongs the suppression of the drug-induced oedema nearly 2-fold (to approximately 24 h per application). The effective dose of dexamethasone delivered with very deformable vesicles into murine skin is reduced >10 times compared with the crème- or lotion-based products. Specifically, less than 0.1 microg cm(-2) dexamethasone in very deformable vesicles suppresses the arachidonic acid-induced murine ear oedema >50%, on the average. Dexamethasone use on the skin in such vesicles extends the duration of drug action fourfold, compared with a commercial crème, i.e. to >48 h per application. Epicutaneous use of glucocorticosteroids in very deformable vesicles also diminishes such drug's abrasion sensitivity and may increase the general robustness of drug effect. Lower frequency of skin treatment, which ensures adequate biological response, is a result of this. Topical corticosteroid delivery with very deformable vesicles, Transfersomes, thus improves the therapeutic risk-benefit ratio, arguably due to better targeting into and longer drug presence in the skin.     

Clonal repopulation in reticular tissues of x-irradiated mice: effect of dose and limb-shielding

Chromosome studies in irradiated mice have indicated that following high sublethal whole-body exposure regeneration of the reticular tissues occurs in a clonal fashion. With increasing doses, from 100 to 700 rads, these organs appeared to be repopulated from fewer and fewer surviving stem cells. In a few instances at the highest dose, the progeny of the same cell apparently differentiated to marrow cells at one site and to lymphoid cells in others, suggestive evidence of a totipotent hematopoietic stem cell in the adult mouse. Chromosome studies in mice receiving 900 rads with one limb shielded have indicated repopulation of the thymus and other reticular tissues by undamaged cells from the shielded marrow. Such marrow-derived cells, perhaps by restoring immunological competence or by non-immunological contact inhibition, could account for the known effect or limb shielding in reducing the incidence of radiation-induced thymic lymphomas.     

The effect of ozagrel sodium on photochemical thrombosis in rat: therapeutic window and combined therapy with heparin sodium

The therapeutic efficacy of ozagrel sodium (ozagrel), alone and in combination with heparin, and its therapeutic time window were studied in a photochemically induced thrombotic cerebral infarction rat model. Cerebral artery thrombosis was induced by irradiating the brain with green light through intact skull using rose bengal as the photosensitizing dye. One set of animals was treated immediately after thrombosis with (1) vehicle, (2) 10 mg/kg ozagrel in saline, intravenously (i.v.), (3) 150 U/kg unfractioned heparin, subcutaneously (s.c.), or (4) ozagrel, i.v. plus heparin, s.c. Infarct volume was significantly smaller and edema was reduced in the ozagrel-treated groups compared to the vehicle-treated group; heparin did not convey additional benefit. In another set of animals, rats were given either vehicle or 10 mg/kg ozagrel in saline, i.v., 60 min or 120 min after induction of thrombosis. Ozagrel reduced infarct volume, but its effect diminished with delayed administration. The therapeutic window was determined to be less than 60 minutes after induction of thrombosis.     

The effect of ethanol upon early development in mice and rats. III. In vivo effect of acute ethanol intoxication upon implantation and early postimplantation stages in mice

Female albino mice (RAP strain) were injected intravenously with absolute alcohol diluted aa by a.d., on days 2, 3 and 4 of pregnancy respectively. Macroscopically pregnant and empty uteri were controlled by microscopic examination. The developmental rate of postimplantation embryos was controlled by a previously reported biometrical method. The acute ethanol intoxication did not influence the postimplantation developmental rate (except for the appearance and development of the allantoic bud). In some of the uteri of the treated females (mainly of those treated on day 4), free blastocysts were found in the uterine lumen on day 9 of pregnancy, supposedly due to the deleterious effect of ethanol intoxication on central and local factors of implantation. Regressive changes of the decidua and consecutive embryonic death found in two litters may be caused by the same deleterious effect or (and) by inflammatory changes present in the endometrium of some control and treated females. The acute ethanol intoxication lowered the mean litter size in all the experimental groups.     

A comparison of assay performance measures in screening assays: signal window, Z' factor, and assay variability ratio

In this article, the authors compare the assay performance measures, signal window, Z' factor, and assay variability ratio. They examine their mathematical formulae for similarities and differences, describe their statistical sampling properties using the results of a computer simulation, and illustrate their use with example data. Based on these results, the authors recommend the Z' factor as a preferred measure of assay performance for screening assays and point out that none of these measures are adequate for characterizing concentration-response assays.     

The therapeutic effect of cortisone,somatotrophic hormone,and hesperedin methyl chalcone in suppressing experimental moniliasis in mice

Summary Female mice infected with moniliasis and treated with a mixture of cortisone, somatotrophic hormone, and hesperedin methyl chalcone showed a marked reduction in the severity of the infection; male mice similarly infected and treated were apparently unaffected. Factors such as the severity of the infection, sex of the animal, and particular doses and proportions used in influencing the response of the infected animal to this mixture are discussed.This paper is part of a study supported by Contract No. NONR 717(00) between the Office of Naval Research, Department of the Navy, and The Creighton University.A preliminary report of this study was presented before the 64th annual meeting of the Nebraska Academy of Sciences (Scherr, 1954b).     

The in vivo dose rate effect of chronic gamma radiation in mice: translocation and micronucleus analyses

The in vivo effects of chronic, ultra low dose rates of gamma radiation in mice were evaluated using fluorescence in situ hybridization and the in vivo micronucleus test. SWR×C57BL/6 mice were divided into nine exposure groups and continuously exposed to 0.5, 2.0 or 4.0 cGy ¹³⁷Cs per day for 30, 60 or 90 days; unexposed control mice were also included. Following exposure, blood samples were taken from each animal and the frequencies of micronucleated polychromatic erythrocytes (MPCE) and micronucleated normochromatic erythrocytes (MNCE) were determined using flow cytometry. Peripheral blood lymphocytes were cultured and analyzed by chromosome painting to determine translocation frequencies. A significant dose rate response was seen in translocations and both MPCE and MNCE. Comparisons were made between the three chronic dose rates and it was determined that there was no significant difference among translocation frequencies for each rate. However, a significant difference was found between the chronic exposures reported here and the fractionated daily exposures reported previously. Dose rate reduction effects, ranging from 3 at low doses to 14 at high doses, were found for chronic versus acute exposures. The possibility of gender effects was investigated in both micronucleus and translocation data. No gender effect was found in translocation induction, but a slight effect was suggested in micronucleus induction.     

The effect of ethanol upon early development in mice and rats. I. In vivo effect upon preimplantation and early postimplantation stages

The preimplantation and early postimplantation effect of chronic alcohol consumption (at least a month before mating and during pregnancy until killing) and of acute ethanol intoxication during the preimplantation period (i.v. infection of ethanol) was studied on albino rats (Wistar) and albino mice (RAP). The main results were as follows: Chronic alcoholization. Rats: significant retardation of preimplantation development and in early postimplantation stages; a tendency of lowering of the mean litter size. Mice: significant increase of the number of preimplantation pathological forms; a tendency of lowering of the mean litter size. Pathological changes show, both in rats and mice, an obvious "litter effect". Acute ethanol intoxication. Rats: significant retardation in some litters, normal or even advanced development in others. This effect differs from the previously reported effect of acute ethanol intoxication during early postimplantation stages. The results obtained attest the prenatal noxious effect of chronic ethanol consumption in both species used and of acute ethanol intoxication during preimplantation development upon early postimplantation development in rats. Within the limits of extrapolation possibilities, they represent a risk signal for other species (including human).     

The effect of ethanol upon early development in mice and rats. II. In vitro effect upon early postimplantation rat embryos

The direct effect of ethanol upon in vitro cultured 9.5 day rat embryos was investigated (2, 4, 8 and 10% ethanol added to the culture medium). The main effects recorded were as follows: 1. Significant increase of the number of "dying" embryos (beating heart without yolk sac circulation); 2. No significant increase of mortality; 3. Significant increase of the number of living embryos with deficient blood circulation; 4. Significant retardation of coiling in living embryos with a significant dose-effect relation, when the effects of 20/00 and 80/00 ethanol were compared; 5. Lowering of the mean somite number in living embryos; 6. Various macro- and macroscopical pathological changes (mainly necrotic areas in the central nervous system).     

The effect of lysergic acid diethylamide on memory in mice]

In experiments on mice of the BALB/c strain a study was made of the influence of lysergic acid diethylamide (LSD) on the retention and reproduction of a conditioned passive avoidance reaction (CPAR). A 0.5-3.0 mg/kg of LSD Injected intraperitoneally 10 min. before the learning procedure, worsened the CPAR retention, while a 0.2 mg/kg of LSD Improved it. The drug (0.2 mg/kg) facilitated the retrieval of the reaction, which did not manifest itself in 24 and 48 hours after learning. This effect depended on the strength of the unconditioned stimulus presented during learning as well as on the time intervals between the moments of learning and testing. Facilitated CPAR retrieval was observed only during the action of the drug and disappeared in 24 hours after its administration. The possible physiological mechanisms of LSD influence on memory processes are discussed.     

新型染料木素磺酸酯的合成及对小鼠血吸虫病肝肉芽肿的影响

为寻找抗血吸虫病的新候选化合物,通过正交实验,高选择性、高产率地合成了染料木素的磺酸酯衍生物。结果表明:小鼠感染血吸虫病,经过衍生物治疗后,由血吸虫导致的肉芽肿面积有不同程度的降低,其中低剂量组降低到23.2%,与溶剂组比较,差异显著(P<0.05),优于原药的27.1%及阳性对照组秋水仙碱的27.0%。说明该化合物对血吸虫导致的肉芽肿有一定抑制作用,该化合物有进一步研究价值。