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At least 19 recordsLinked to original sources
PubMed1995

Tilorone-induced lysosomal storage of sulphated glycosaminoglycans can be separated from tilorone-induced enhancement of lysosomal enzyme secretion.

This investigation deals with a drug side-effect. The immunomodulatory drug tilorone (2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one) and congeners induce lysosomal storage of sulphated glycosaminoglycans (GAGs) in animals and in cultured cells. At high tilorone concentrations, GAG storage in cultured fibroblasts was previously reported to be accompanied, and presumably caused by, disturbance of intracellular targeting of lysosomal enzyme precursors, which leads to enhanced secretion and thus loss of lysosomal enzymes. The purpose of the present study was to examine whether the GAG storage induced in cultured bovine fibroblasts by low tilorone concentrations is also accompanied by enhanced lysosomal enzyme release. Enhanced secretion of beta-hexosaminidase (EC 3.2.1.52) was taken as indicating the intracellular mistargeting of lysosomal enzyme precursors. Dose-response curves were established for (a) the intracellular accumulation of 35S-GAGs and (b) the release of beta-hexosaminidase after exposure (72 hr) to tilorone (1-35 microM). For positive controls, the classical lysosomotropic agents NH4Cl (1-30 mM) and chloroquine (1-60 microM) were used. With NH4Cl, 35S-GAG storage was accompanied by enhanced enzyme release throughout the concentration range (EC50 at 3.3 mM for either effect). With chloroquine, low concentrations (< or = 5 microM) caused a small increase in 35S-GAG accumulation without abnormal enzyme secretion; at higher concentrations both drug effects were produced (EC50 around 15 microM for either effect). With tilorone, low concentrations (< or = 5 microM) caused marked 35S-GAG accumulation without enhancement of enzyme release. The EC50 for tilorone-induced 35S-GAG storage was 3 microM, as opposed to 15 microM for enzyme release. The results indicate that GAG storage induced by low concentrations of tilorone is due to mechanisms other than mistargeting and loss of lysosomal enzymes. On the basis of previous results it may be hypothesized that tilorone and other symmetrically substituted dicationic compounds form complexes with the polyanionic GAG chains and thereby impair their enzymic degradation.

Ammonium Chloride↗
PubMed1979

[Carbonyl derivatives of tilorone. Part 2: On the cancerostatic activity of carbonyl derivatives of tilorone (author's transl)].

A series of carbonyl derivatives of tilorone was synthetized by reaction with appropriate amino compounds, mainly hydrazines and hydrazides. The condensation products obtained were tested for cancerostatic activity against the murine leucaemia L 1210 and the Walker carcinosarcoma of the rat. Only three of the substances under investigation (1a, 5, 13) proved active against the Walker carcinosarcoma, one of which (5) being comparable to tilorone. No activity against L 1210 was observed, even tilorone exerted no effect. The reduction in activity against the Walker carcinosarcoma which resulted from the carbonyl substitution might be caused by a decrease in the ability to intercalate into DNA.

Animals↗
PubMed1992

Prevention of tilorone developmental toxicity with progesterone.

The immunomodulator tilorone hydrochloride was administered (gastric intubation) once to time-pregnant Upj:TUC(SD)spf (Sprague-Dawley) rats in four experiments. In experiment 1, tilorone (250 or 500 mg/kg) was administered on day 10 of gestation. The dams were killed 4 or 72 hr after dosing. Interferon-like activity and drug levels were determined in maternal blood, spleen, and thymus, as well as in the embryos. In experiment 2, the test groups received progesterone (2 mg/kg), or tilorone (200 or 400 mg/kg), or progesterone and tilorone. The dams from each group were killed 24 or 48 hr after receiving tilorone. Experiment 3 was similar to experiment 2, except that the dams were killed on gestation day 20. In experiment 4, tilorone (400 mg/kg) was administered on gestation day 17, 18, or 19, and the dams were killed 24 hr after dosing or on gestation day 20. In all four experiments, tilorone-related maternal toxicity (regardless of whether progesterone also was administered) was observed, as characterized by marked decreases in weight gain, the occurrence of clinical signs, and in experiment 1 by decreased thymus weights, 72 hr post-dosing. Dose-related increases in the mean number of dead embryos and in serum interferon titers occurred 72 hr postdosing. In experiment 2, there was an increase in the number of dams in the 400-mg/kg (tilorone only) group with dead embryos only, 24 hr postdosing; similar results occurred in both the 200- and 400-mg/kg groups, 48 hr postdosing. However, in the groups that also received progesterone, a partial prevention of such embryolethality was evident. In experiment 3, embryotoxicity again was observed in both tilorone-treated groups, whereas several of the dams that were also given progesterone through day 19 of gestation experienced at least a partial prevention of the embryolethal effects of tilorone. In experiment 4, no fetotoxicity was observed despite the severe maternal toxicity evident.

Animals↗
PubMed1972

Tilorone hydrochloride: an oral interferon-inducing agent.

Tilorone hydrochloride characteristically induces an unusually delayed and prolonged interferon response not commonly associated with other synthetic inducers. Maximum circulating interferon levels of 8,000 to 10,000 units/ml were detected 12 hr postinoculation and persisted for up to 30 hr after administration of tilorone. The fact that both oral and intraperitoneal injections of tilorone induce a similar response suggests that this delay is not based on the time required for adsorption from the gastrointestinal tract. In vitro, tilorone failed to induce detectable levels of interferon in either mouse peritoneal lymphocyte or macrophage cell cultures. Furthermore, interferon production could not be detected in the upper gastrointestinal tract after oral administration of tilorone. The striking suppression of interferon production in X-irradiated mice suggested that lymphatic tissue may be a source of interferon in response to tilorone. This concept was not supported, however, by experiments utilizing antilymphocyte serum (ALS). Tilorone induced comparable levels of interferon in both ALS-treated and control animals which had received normal serum, even though the ALS-treated mice had decreased spleen weights and peripheral lymphocyte counts. These data suggest that a radiosensitive cell population other than lymphocytes may be an important factor in the capacity of the host to produce interferon in response to tilorone. Mice which received repeated injections of tilorone developed a severe state of hyporeactivity. The degree of hyporeactivity was particularly striking when compared to that induced by polyinosinic acid:polycytidylic acid and emphasizes one of the major obstacles confronting interferon inducers as chemotherapeutic agents.

Animals↗
PubMed1984

Effects of the interferon inducing agents tilorone and polyriboinosinic acid . polyribocytidylic acid (poly IC) on the hepatic monooxygenase systems of pregnant and fetal rats.

Interferon inducing agents, including tilorone and polyriboinosinic acid . polyribocytidylic acid (poly IC), are known to depress hepatic cytochrome P-450-dependent monooxygenase systems and the induction of these systems by phenobarbital (PB) and 3-methylcholanthrene (MC) in mature male rats. The current study investigated the effects of tilorone and poly IC on the cytochrome P-450 systems of non-induced, PB-induced, MC-induced and pregnenolonecarbonitrile (PCN)-induced pregnant rats and their fetuses. Pregnant rats received either tilorone or poly IC and saline, PB, MC or PCN, and microsomes from their livers and those of their fetuses were examined for cytochrome P-450 content, aminopyrine (AP) N-demethylase activity and benzo[a]pyrene (BP) hydroxylase activity. The generalization can be made from these studies that, when the interferon inducing agents caused changes in cytochrome P-450 content or monooxygenase activities of either induced (PB, MC or PCN) or non-induced (saline) animals, decreases were seen in maternal livers and increases in fetal livers. Thus, in maternal livers tilorone depressed cytochrome P-450 and AP N-demethylase activity in non-induced and PB-, MC- and PCN-induced rats and BP hydroxylase activity in the induced animals; BP hydroxylase activity was not depressed in non-induced maternal livers. Poly IC depressed cytochrome P-450 and AP N-demethylase activity in non-induced and PB-induced rats but not in PCN-induced animals. BP hydroxylase was depressed by poly IC in both PB- and PCN-induced animals. Fetal hepatic cytochrome P-450 and monooxygenase activities were increased by tilorone in PB- and PCN-induced rats but not in non-induced or MC-induced animals. Poly IC increased cytochrome P-450 and both monooxygenase activities in PB- and PCN-induced fetal livers, whereas only BP hydroxylase activity was increased in the fetuses of non-induced rats. Several possible explanations are offered for the opposite effects produced by interferon inducing agents in maternal and fetal livers. Unlike maternally administered tilorone, which induced fetal cytochrome P-450 and monooxygenase activities in the liver, intrauterine tilorone depressed cytochrome P-450 and had no effect on AP N-demethylase or BP hydroxylase activities in the fetal liver. Intrauterine poly IC was without effect on the cytochrome P-450 systems of the fetal liver. Treatment of pregnant rats with tilorone on days 17-20 of gestation inhibited normal maternal weight gain and produced overt signs of toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminopyrine N-Demethylase↗
PubMed1995

Tilorone-induced lysosomal storage of glycosaminoglycans in cultured corneal fibroblasts: biochemical and physicochemical investigations.

Tilorone (2,7-bis[2-(diethylamino)ethoxy]-fluoren-9-one) and several other bis-basic compounds are known to induce lysosomal glycosaminoglycan (GAG) storage. The responsible pathomechanism has not been elucidated yet. The assumption of an unspecific disturbance of lysosomal proenzyme targeting due to elevation of endosomal pH is opposed by the hypothesis of formation of a complex between tilorone and GAGs within the lysosomes, which renders GAGs indigestible to glycosidases. In cultures of bovine corneal fibroblasts the amounts of intracellular GAGs [dermatan sulphate (DS), heparan sulphate (HS) and chondroitin sulphate (CS)] were quantified. The fibroblasts were exposed to tilorone (5 microM), which was found to be readily taken up by the cells and to be accumulated within acidic compartments to finally achieve millimolar concentrations. Under these conditions the GAG storage is predominantly due to the accumulation of DS; however, the DS secretion into the culture medium was not affected. The HS accumulation was much less pronounced, accounting only for 3% of total GAG storage. Ammonium chloride (10 mM), which is known to diminish lysosomal enzyme activity by interfering with the mannose 6-phosphate receptor-mediated transport, prevents both HS and DS breakdown. By means of NMR spectroscopy it was shown that tilorone itself tends to display a concentration-dependent aggregation which was enhanced in the presence of GAGs. The diethylamino groups of tilorone interact physicochemically with DS, and to a smaller extent with HS, but not with chondroitin 4-sulphate. Thus, the strength of the interaction between tilorone and the different GAGs in vitro correlates with the potency of tilorone to inhibit the breakdown of the individual GAGs in cultured bovine fibroblasts. The results support the hypothesis of a specific interaction between tilorone and particular GAGs, rendering these resistant to enzymic degradation.

Ammonium Chloride↗
PubMed1993

Generation and control of metastasis in experimental tumor systems; inhibition of experimental metastases by a tilorone analogue.

The role of the chemical compound RMI 10,874DA (3,6-bis[2-(dimethylamino)-ethoxyl]-9H-xanthene-9-one dihydrochloride) in the abrogation of the metastatic spread of tumor cells was studied. Pre-treatment of BALB/c mice with the RMI 10,874DA compound (referred to below as tilorone analogue) completely eliminated lung colonization of an H-2-negative (GR9.B9) MCA-induced fibrosarcoma clone in an experimental metastasis assay. Other murine tumors, including H-2-positive and H-2-negative chemically induced fibrosarcoma clones and B16 melanoma, were also sensitive to the treatment; orally administered tilorone analogue given one day before the i.v. injection of tumor cells markedly inhibited lung colonization. The effect was not due to direct toxicity of tilorone analogue on tumor cells, but instead it was dependent on NK cells; this was suggested by the finding that anti-asialo GM, treatment of mice abrogated the effect of tilorone analogue. Kinetic studies of splenic NK activity in tilorone-treated mice showed a rapid boosting of NK-cell activity, the greatest stimulation occurring the day before removal of splenocytes for 51Cr-release assay against YAC-I target cells. These kinetics correlated with the inhibition of in vivo lung colonization after tilorone analogue treatment. Inhibition of experimental tumor metastasis was dose-dependent and was observed when animals were treated the day before or the day after tumor-cell injection. Furthermore, repeated treatment of mice with this tilorone analogue significantly reduced lung colonization.

Animals↗
PubMed1987

Enhancing effects of tilorone on collagen arthritis and humoral immune response to type II collagen.

The effect of tilorone, which is known to suppress adjuvant arthritis, on the induction of collagen arthritis in rats was investigated. Combined data of the present experiments show that all of the tilorone-treated rats except one in the lowest dosage group developed arthritis but that the incidence of arthritis in the tilorone-treated groups was not significantly different from that of the control group. The results also show that the two higher dosages (12.5 and 25 mg/kg/day) of tilorone caused a significant increase in the severity of collagen arthritis. Humoral immune response to type II collagen was significantly augmented in these two higher dosage groups; however, delayed-type hypersensitivity response to type II collagen was suppressed while tilorone was administered continuously. In addition, treatment with tilorone caused a significant increase in the concentration of anticollagen IgG extractable from the joint tissue. Anticollagen IgG subclass analysis revealed that the major subclass was IgG2a in both the serum and paw extract, with minor amounts of IgG2b, IgG2c, and IgG1. The response of all these subclasses was almost equally activated by tilorone treatment.

Animals↗
PubMed1996

Tilorone-induced lysosomal lesions: the bisbasic character of the drug is essential for its high potency to cause storage of sulphated glycosaminoglycans.

The immunomodulatory agent tilorone -2,7-bis-[2-(diethyl-amino)ethoxy]fluoren-9-one- and congeners are potent inducers of lysosomal storage of sulphated glycosaminoglycans (GAGs) in animals and cultured fibroblasts of animals and man. All potent inducers of GAG storage hitherto described are bisbasic polycyclic aromatic compounds. They are accumulated in lysosomes and disturb the degradation of GAGs, mainly dermatan sulphate. It has been proposed that the drugs cross-link the polyanionic GAG chains giving rise to undergradable drug-GAG complexes. This hypothesis implies that the bisbasic character of the drug molecules is essential for the side effect in question. In the present study, this was tested by comparing tilorone and its monobasic derivative (MT) with respect to (i) induction of GAG storage in cultured bovine corneal fibroblasts and (ii) physicochemical interactions with GAGs in vitro. The intralysosomal concentration of MT achieved after 1-3 days was of the same order of magnitude as previously shown for tilorone. Nevertheless, under conditions that did not enhance the secretion of a lysosomal enzyme (beta-hexosaminidase, EC 3.2.1.52), the ability of MT to cause storage of [35S]GAGs was significantly lower than that of tilorone. Morphological observations showed that MT was much more potent in causing lysosomal storage of polar lipids than of GAGs. CD spectroscopy with tilorone revealed that the presence of GAGs caused the primarily achiral drug molecules to display CD. This suggested a helical orientation of the tilorone molecules within GAG-drug complexes, and short intermolecular distances which allowed electronic coupling of the aromatic ring systems of adjacent drug molecules. In contrast, MT failed to display any induced optical activity, indicating the absence of highly ordered GAG-drug complexes. In conclusion, the present results show that the substitution of the planar aromatic ring system with two basic side chains is essential for the high potency of tilorone in inducing lysosomal GAG storage. This is paralleled by, and presumably causally related to, strong physicochemical interactions with GAGs.

Adjuvants, Immunologic↗
PubMed1986

Effect of the immunomodulator tilorone on antipyrine disposition in the rat.

A wide variety of immunomodulators, including the synthetic interferon inducer tilorone (2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one), have been shown to inhibit cytochrome P-450-dependent drug metabolism in vitro. In an effort to determine if tilorone also inhibits drug metabolism in vivo, we examined the effect of this agent on the disposition of antipyrine in the rat. Administration of tilorone hydrochloride (50 mg X kg-1 X d-1) 4 d resulted in a 42% reduction in antipyrine clearance and a 71% increase in plasma half-life. Administration of a single dose of tilorone hydrochloride (50 mg/kg) 48 h prior to antipyrine was found to cause a similar alteration in antipyrine clearance and half-life. Both treatment regimens were also found to produce a substantial weight loss in the pretreated animals. Preliminary studies indicated that tilorone treatment reduced food and water consumption in the rat. Therefore, the effect of a 75% decrease in food and water consumption on antipyrine disposition was also examined. This magnitude of restriction had no detectable effect on antipyrine elimination. Thus, tilorone results in a substantial reduction of the in vivo metabolic clearance of antipyrine and appears to be a useful compound for studying the dynamic interaction between the drug metabolizing and immune systems in vivo.

Animals↗
PubMed1983

Impaired macrophage functions as a possible basis of immunomodification by microbial agents, tilorone and dimethyldioctadecylammonium bromide.

Four microbial and two chemically defined immunomodulating agents namely viable BCG, killed Mycobacterium butyricum, killed Lactobacillus plantarum, zymosan, tilorone, and dimethyldioctadecylammonium bromide (DDA) were studied for their effects on macrophage functions in vitro and in vivo. All agents induced a dose-dependent mortality of macrophages as determined by trypan blue exclusion. DDA and especially tilorone were rather toxic for macrophages in vitro. All agents except tilorone and DDA inhibited phagocytosis of yeast cells and uptake of acridine orange in vitro at doses which killed up to about 30% of the macrophages. DDA and tilorone had no effect at similar doses. All agents but zymosan inhibited the spreading of macrophages. No interference with the fusion of lysosomes and yeast cell-containing phagosomes could be observed. The activity of the mononuclear phagocytic system (MPS) in vivo as measured by carbon clearance was stimulated by all substances within twenty-four hours. All agents but DDA and tilorone enhanced non-specific bacterial resistance. As demonstrated previously for DDA, tilorone could serve as adjuvant for induction of specific resistance to Listeria monocytogenes. The results are discussed in relation to other data on influencing of macrophage functions and on immunomodification. It is concluded that hampered antigen destruction by local macrophage suppression attended with MPS stimulation might be a basic mechanism for adjuvanticity exerted by these agents.

Adjuvants, Immunologic↗
PubMed1989

Mucopolysaccharidosis and lipidosis in rats treated with tilorone analogues.

The experimental immunomodulatory agent tilorone was previously reported to induce generalized mucopolysaccharidosis (lysosomal storage of sulfated glycosaminoglycans) and lipidosis in rats. While lipidosis is a side effect common to many cationic amphiphilic compounds, none of them except tilorone has been known to cause mucopolysaccharidosis in intact animals. The purpose of the present histochemical and ultrastructural study was to examine whether or not mucopolysaccharidosis can be induced by tilorone analogues. Three analogues were selected and administered to rats in short-term and subchronic experiments, and liver, spleen, kidney, and cornea were examined. The analogues caused generalized cellular lesions which had the same histochemical and cytological characteristics and the same distribution as the lesions produced by tilorone. The results show that the ability to induce mucopolysaccharidosis is not a unique property of tilorone; this drug side effect should be taken into account when developing new drugs with molecular structures resembling that of tilorone.

Animals↗
PubMed1980

Mechanism of cellular suppression induced by oral tilorone treatment of mice.

Specific-pathogen-free B6D2 F1 hybrid mice were treated orally with tilorone hydrochloride (100 mg/kg of body weight per day) and infected with sublethal doses of Listeria monocytogenes, Salmonella enteritidis, Mycobacterium bovis (BCG Pasteur), or M. tuberculosis Erdman. Daily tilorone treatment inhibited the cell-mediated response to all of the intracellular parasites, and most of the mice succumbed to the challenge. Tilorone suppressed delayed hypersensitivity responses to the microbial sensitins as well as to sheep erythrocytes. However, humoral responses (immediate hypersensitivity reactions) were stimulated. The types of growth curves obtained in the tilorone-treated mice were quite different from those observed in T-cell-depleted mice and tended to resemble those seen in sublethally irradiated (400 rads) animals. Leukocyte counts were depressed 10-fold by daily tilorone treatment. Both monocyte and granulocyte (but not large-lymphocyte) counts were depressed. There was an initial drop in small-lymphocyte counts with a later recovery phase. Tilorone treatment reduced the granulomatous response within the Salmonella-infected liver, suggesting that the drug interferes with the mobilization of the mononuclear defenses within the normal host.

Animals↗
PubMedDate not supplied

Decrease in the activity of the drug-metabolizing enzymes of rat liver following the administration of tilorone hydrochloride.

Tilorone hydrochloride, 2,7-bias(2-(diethylamino)ethoxy(fluoren-9-one dihydrochloride, has been studied to determine its effect on the drug-metabolizing enzymes of the liver of male Charles River CD strain rats. Single and multiple doses of tilorone-HCl, 100 mg/kg/day po, were used. Most experiments were performed 24 hr after the last dose, except for a study 5 hr after dosing, and those in which the duration of effects of tilorone hydrochloride were determined. The hexobarbital sleeping time was prolonged after both single doses and four doses of tilorone hydrochloride. The 4-dose regimen prolonged the zoxazolamine paralysis time but the single dose did not. A decrease in microsomal protein was observed after the single- and 4-dose regimens but not after 21 daily doses of tilorone-HCl. Cytochrome P-450 content of microsomes was decreased by the single doses, 100 and 250 mg/kg po, and by 4 and 21 doses of 100 mg/kg/day po. Activities of aminopyrine demethylase and hexobarbital oxidase also were decreased by the above regimens, but the activity of hexobarbital oxidase was affected more markedly. Electron micrographs of rat liver, after treatment with tilorone-HCl, 100 mg/kg/day for 21 days, revealed many membranous structures in the form of whorls.

Aminopyrine N-Demethylase↗
PubMed1975

Comparison of the ability of small molecular interferon inducers: tilorone and acridine drugs.

The antiviral activity and induction of interferon-like substance by mepacrine (quinacrine, Atabrine) and Acranil in mice, described previuosly, was studied in more detail and compared with tilorone. The serum substance induced by Acranil was characterized as mouse interferon. Acranil, given parenterally, proved to be as strong as tilorone regarding interferon stimulation, in spite of the presence of only one side chain in the Acrainl molecule. Mepacrine was found to be a wealer interferon inducer than either tilorone or Acranil. The mode of interferon induction by Acranil and tilorone (effect of metabolic inhibitors, hyporesponsiveness to repeated doses, correlation between acute toxicity and antiviral activity, failure of effectiveness in chicks and chicken embryo tissue culture) was found comparable. However, the body temperature reactions of mice to the drugs were different: a striking hypothermic effect of tilorone, a lower one of mepacrine and the absence of body temperature depression by Acranil was observed.

Acridines↗
PubMed1991

Dissociation between antiinflammatory action of tilorone and its interferon inducing activity.

A relation between antiinflammatory action of tilorone and its interferon inducing activity was studied in rats. Tilorone (20-100 mg/kg, p.o.) was dose-dependently effective on both carrageenin oedema and passive Arthus, suggesting that the pharmacological property of the compound is different from nonsteroidal antiinflammatory medicaments which were weak inhibitors of passive Arthus. The antiinflammatory action of tilorone had a time-lag and priming with tilorone 24 hrs prior to inflammatory insult was required to demonstrate maximal efficacy. This time course change was similar to that of serum interferon level. In addition, a high correlation was observed between the antiinflammatory activity and the serum interferon level. However, the antiinflammatory action was scarcely affected even if the serum interferon level was remarkably lowered by treatment of an inhibitor of protein biosynthesis, cycloheximide. These findings suggested that the antiinflammatory action of tilorone could be dissociated from its interferon inducing activity.

Animals↗
PubMed1984

Effects of the interferon inducing agents tilorone and polyriboinosinic acid . polyribocytidylic acid (poly IC) on the hepatic monooxygenase systems of the developing neonatal rat.

This paper describes the effects of the interferon inducing agents tilorone and polyriboinosinic acid . polyribocytidylic acid (poly IC) on the postnatal development of hepatic cytochrome P-450-linked monooxygenase systems of male rats from birth through early adolescence. The administration of tilorone to rats on days 1 and 2 postpartum modified the changes in the activities of hepatic monooxygenase systems that occur normally during the first four days postpartum. Thus, aniline hydroxylase activity, which develops very rapidly during the first 2 days postpartum, was depressed markedly by tilorone, ethylmorphine N-demethylase activity was depressed moderately, and benzo[a] pyrene hydroxylase, normally the slowest of the three monooxygenase activities to develop, was induced. These changes in monooxygenase activities occurred without a significant change in the cytochrome P-450 content. These observations suggest that not all species of neonatal cytochrome P-450 are affected equally by tilorone administration. By day 7 postpartum, the cytochrome P-450 content and all three monooxygenase activities were depressed in rats that had received tilorone on days 1 and 2 postpartum. All three monooxygenase systems were depressed by the administration of a single dose of poly IC (10 mg/kg) in 1-, 2-, 21-, 28- and 56-day-old rats. The length of the period between maximal depression and complete recovery of cytochrome P-450 systems was shown to be a function of the age of the rat; it increased from about 6 hr in 1-day-old rats to 48 hr in 56-day-old rats. Protein is synthesized more rapidly and degraded more slowly in neonate than in adult animals; this may account for the more rapid recovery of poly IC-induced depression of monooxygenase systems in neonates.

Aging↗
PubMed1978

Modulation of the acquisition and expression of immunity by Tilorone: I. Delayed-type hypersensitivity responses.

The chronic administration of Tilorone [(2,7-bis(diethylamino)ethoxy]fluoren-9-one) with antigen seems to prevent the generation of DTH effector cells. The administration of Tilorone proximal to DTH challenge blocks the expression of DTH. By local transfer of DTH effector cells, this latter effect can be shown to be due to the lack of nonspecific inflammatory cells. By the use of both systemic and local transfer systems, it is also shown that specific DTH effector cells from animals treated with Tilorone are unable to circulate in the normal manner. Overall, these experiments suggest that Tilorone does not block the generation of DTH effector cells, but it does greatly alter the expression of DTH. The relation between these effects and the known interferon induction capacity on Tilorone remains unclear.

Animals↗