In vitro and in vivo kinetic interactions of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid with thalidomide and diclofenac
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Diclofenac
The bacterial extract IMOCUR is described as an in vivo stimulant of antibody production during animal testing and human clinical trials. Using a slightly modified procedure (13) dealing with in vitro immunoglobulin production by C57B1/6 mouse spleen cells, we have shown that IMOCUR potentiates spontaneous IgM production. In order to explore the putative relation between this in vitro activity and the current in vivo control test (stimulation of plaque-forming cell production after sheep red blood cell injection to Balb/c mouse), we have assayed 10 lyophilisates in vitro and in vivo before and after heat inactivation (80 degrees C, 7 days in a saturated water atmosphere). Results have shown that this treatment inhibits, respectively, totally and partially in vivo and in vitro activities. Thus the in vitro technique seems to be appropriate for the control of activity of the various batches of IMOCUR. Experiments are under way to clarify the mathematical correlation which may exist between the in vitro and in vivo experiments.
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A qualitative comparison of the in vitro and in vivo activity on β-hemo1ytic streptococcus of 126 compounds consisting of sulfanilamide derivatives, sulfonamides, suifones, sulfoxides, sulfides and certain miscellaneous compounds has been made. It has been shown that no compound is active in vivo unless it is active in vitro or can be decomposed in the animal body to a compound which would be active in vitro , and that compounds can be active in vitro but inactive in vivo.
Sulfanilamide
Sulfonamide
Active compound
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The endpoints of in vivo and in vitro assays applied to cells after exposure to a potential oncogenic transforming agent are cellular tumorigenicity and transformation. Tumors are failures of in vivo growth control; transformations are failures of in vitro growth control. Many agents cause tumors in vivo, many agents transform normal cultured cells, and some agents do both. However, even when caused by a single agent, the in vivo and in vitro endpoint assays show only a partial overlap. That is, some but not all tumors will grow as transformed cells in culture, and some but not all in vitro transformants will be tumorigenic on injection into susceptible animals (Shin et al., 1975). Recently, we have described a subset of in vitro phenotypic changes that correlate with in vivo tumorigenicity (Steinberg et al., 1979; Barrett et al., 1979; Pollack, 1981). In this chapter, we will describe recent studies on one of the in vitro changes linked to tumorigenicity, the disruption in organization of cyto-skeletal actin.
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To determine the optimal condition of the clonogenic assay, the antitumor activities of 5-fluorouracil (5-FU) in vitro and in vivo were investigated from a pharmacodynamic viewpoint using 8 human carcinoma xenografts. The clonogenic assay was performed by the continuous exposure method, and the antitumor effects were evaluated by the colony survival rates (T/Cs). The in vivo experimental chemotherapy was also performed by the nude mouse system, and the results were evaluated by the T/C ratios of the tumor weights. For pharmacokinetic analyses, the area under the concentration curves (AUCs) of 5-FU in vitro and in vivo were computed. The T/Cs of 5-FU were highly correlated to the AUCs both in vitro and in vivo. By using these AUC-T/C correlations, the concentration of 5-FU in the clonogenic assay to predict the T/C of the maximum tolerated dose in mouse was calculated to be 3 micrograms/ml mathematically. This concentration was then verified by the clonogenic assay, where T/Cs in vitro could successfully correspond to the T/Cs in vivo. (The predictable rate was 87.5%) From these results, this pharmacodynamic comparison between in vitro and in vivo chemosensitivities was thought to be a promising method for determining the conditions of the clonogenic assay.
Clonogenic assay
Pharmacodynamics
In vitro toxicology
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Abstract Poly-[(trans-1,2-diaminocyclohexane) platinumj-carboxyamylose (“poly-plat“) is a second generation analog of cisplatin which enhances the immune system with greater efficacy in vitro and in vivo “Poly-plat” contains 1/5 the platinum of CDDP and demonstrates less toxicity. In order to understand the mechanism of action of this compound an in vitro and in vivo study was performed. Swiss Webster mice and isolated murine peritoneal macrophages were treated with “poly-plat” (10 mg/kg). The Swiss Webster mice were given bolus injections and sacrificed at 2 and 12 days. Peritoneal macrophages were then isolated and allowed to incubate in culture for 24 h. Peritoneal macrophages were also isolated from normal mice and treated with the drugs for 2 h. After treatments the macrophages were placed in fresh media and allowed to incubate 24 h. Supematants were isolated at various times during culture for immunocytochemical analysis. Both in vitro and in vivo studies showed enhanced immunostimulation after their respective treatments.
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The ointments with marked insulin J125 were prepared on suitable ointment bases. The dynamics of the released insulin from ointment in vitro and in vivo was analyzed. It has been noticed that the most of the marked insulin J125 was released in vitro and in vivo from eucerin and that there is a correlation between the amount of released insulin from ointment basis in vitro and in vivo.
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SUMMARY Highly specific antibodies to mouse macrophages can be obtained in rabbits following immunization with pure cultures of mouse macrophages. Antimacrophage serum prepared in the manner described reacted specifically with macrophages in vitro and interfered with the initiation of the immune response to trinitrophenol sullonate in vivo.
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An in vitro method and an in vivo method of excystation were compared to determine the most useful method for the retrieval of Giardia duodenalis isolates. Cysts from 11 Giardia strains were used. In vitro excystation produced motile trophozoites in 16 sets, while in vivo excystation produced trophozoites in all of the 21 comparative sets of excystations. Few cultures were lost because of contamination by either method (17% of in vitro-derived trophozoites versus 23% of in vivo-derived trophozoites; P greater than 0.05). Both methods demonstrated comparable isolate retrieval rates (15% of in vitro-derived trophozoites adapting to culture compared with 29% of in vivo-derived trophozoites; P greater than 0.05), although analysis of the strains retrieved showed that two isolates were retrieved from in vitro excystation alone, compared with four from in vivo excystation. Analysis that included results of extra in vivo cultures showed that a total of nine isolates were retrieved by using this type of excystation. Despite the disadvantages of cost and labor, in vivo excystation appears to be more useful than in vitro excystation for isolate retrieval at the present time.
Giardia
Giardia lamblia
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A series of 2-substituted trans-1,2-epoxyethanesulfonamides (1T), ethynesulfonamides (2), and their carboxamide analogues 3 (cis and trans) and 4 were evaluated for their antifilarial activity, first in vitro against the infective larvae of the filaria Molinema dessetae, then in vivo against the same filaria in Proechimys oris, its natural host. On the whole, compounds 2 displayed a high level of activity in vitro, while 4 showed a wider range and 3 were virtually inactive. The modest activity found within the series 1T was assumed to be due, in part, to the instability of the products under the conditions of the biological tests. Five new compounds within the series 1T, 2 and 4 showed a macrofilaricidal activity in vivo. There is no clear correlation between in vivo and in vitro data. It was observed, however, that within the series 2 and 4 all the compounds active in vivo were among the most potent compounds in vitro. Nevertheless, the in vitro model, although of limited value, could help in selecting compounds for further evaluation within a given series.
Carboxamide
Structure–activity relationship
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