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At least 19 recordsLinked to original sources

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↗

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↗

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↗

PubMed1976

Skin and heart allograft prolongation in tilorone-treated rats.

Tilorone is a synthetic amino-alkoxyfluorenone with demonstrated antiviral and antitumor properties. This study gives evidence for immunosuppressive properties of the substance as well. Buffalo rats (AgB6) received skin grafts from rats of the Fischer (AgB1) strain. Control animals rejected in 9.9 +/- 1.1 days, compared to 13.7 +/- 2.3 days for recipients treated with Tilorone. Steroids when combined with Tilorone further prolonged skin allografts to 16.7 +/- 2.6 days. Heart allografts from Fischer (AgB1) and Brown-Norway (AgB3) to Lewis (AgB1) also were performed. In the Fischer to Lewis combination, allograft survival was prolonged from 14.7 +/- 1.0 to 31.0 +/- 3.8 days. In the Brown-Norway to Lewis combination, treated rats rejected in 10.2 +/- 1.4 days versus 6.6 +/- 1.1 days for controls. Increased levels of cytotoxic antibody specific to lymphocytes of the donor strain were noted in Tilorone-treated animals. The mechanism by which Tilorone prolongs allografts may well involve a combination of interferon production and specific suppression of thymus-derived lymphocytes.

Animals↗

PubMed1978

The antipyretic effect of tilorone hydrochloride in the cat.

1 The antipyretic activity of tilorone hydrochloride was studied in conscious, unrestrained cats provided with implanted jugular venous catheters, third cerebral ventricular (i.c.v.) cannulae and retroperitoneal thermocouples. 2 In afebrile animals, 10 mg/kg i.v. or 1 mg i.c.v. tilorone hydrochloride did not alter body temperature, but 20 mg/kg i.v. or 2 to 5 mg i.c.v. caused hypothermia and various behavioural responses. 3 Non-hypothermogenic doses of tilorone (i.v. or i.c.v.) antagonized hyperthermic responses to leucocytic pyrogen (i.v. or i.c.v.), bacterial pyrogen (i.c.v.) and sodium arachidonate (i.c.v.) but did not antagonize prostaglandin E1 (i.c.v.). 4 These results indicate that tilorone has an antipyretic action within the central nervous system that is distinct from its hypothermogenic action. Although there is no published evidence to indicate that tilorone can inhibit prostaglandin synthesis peripherally, its ability to reduce hyperthermic responses to arachidonate suggests that it can inhibit prostaglandin synthesis within the brain.

Animals↗

PubMed1977

Comparation interferon- inducing and antiviral properties of 2-amino-5-bromo-6-methyl-4-pyrimidinol (U-25,166), tilorone hydrochloride, and polyinosinic-polycytidylic acid.

2-Amino-5-bromo-6-methyl-4-pyrimidinol (U-25,166), polyinosinic acid-polycytidylic acid [poly(I:C)], and tilorone HCl induced high levels of serum interferon in mice. Each consequently protected mice against infection with several viruses. After daily injection of inducer, mice developed a reduced interferon response (hyporeactivity) to each compound. However, hyporeactivity developed more slowly to U-25,166 and poly(I:C) than to tilorone HCl. After onset of hyporeactivity, 5 to 6 days without each inducer were required before normal serum interferon levels could be stimulated. Animals also developed a hyporeactive state as a consequence of Semliki Forest or encephalomyocarditis virus infections. By day 2 of either infection, mice had a suppressed interferon response to tilorone HCl, but remains responsive to poly(I:C) or U-25,166 until day 4. In vivo, poly(I:C) stimulated interferon production in a variety of cells and organs, whereas the tilorone HCl and U-25,166 responses involved a nonlymphoid component of the reticuloendothelial system. In vitro, poly(I:C) induced interferon in a variety of murine cells, U-25,166 was active in murine thymus and spleen organ cultures, and tilorone was inactive. These data indicate that U-25,166 is an interesting low-molecular-weight interferon inducer.

Animals↗

PubMed1976

Effect of tilorone on susceptibility of mice to primary or secondary infection with Listeria monocytogenes.

Subcutaneous administration of the drug tilorone did not increase the susceptibility of CD-1 male mice to intravenous or intraperitoneal infection with an alpha-toxin-deficient mutant of the Smith diffuse strain strain of Staphylococcus aureus. In contrast, a single injection of this drug greatly increased the susceptibility of mice to an intravenous or an intraperitoneal infection with Listeria monocytogenes, an intracellular parasite. The effects of tilorone, which were maximal when the drug was administered on the day of the listerial challenge or one day thereafter, were reflected by relatively lower mean lethal dose values and enhanced proliferation of Listeria in the spleen and liver. The ability of tilorone, administered at the time of listerial challenge, to decrease the resistance against the challenge was partially abrogated by previous administration of the same drug. Tilorone, administered at the time of immunization with a very small number of viable Listeria, greatly enhanced the potency of the immunization. On the other hand, tilorone, administered to Listeria-immunized mice near to the time of a listerial challenge, slightly reduced the protective effects of the prior immunization.

Animals↗

PubMed1978

Effect of tilorone hydrochloride on hepatic disposition of sulphobromophthalein (BSP) in the rat.

1. Biliary excretion of sulphobromophthalein (BSP) was studied in male rats after oral administration of tilorone HCl, an anti-viral and anti-tumour agent. 2. The stimulation of bile flow by BSP was decreased 1 h after tilorone administration; this decrease was no longer apparent 24 h later but a fall of basal bile flow was noted at that time. No changes in bile flow were observed 7 days after this single dose. 3. Repeated dosing with tilorone produced a dose-dependent increase in hepatic concentration of unchanged and metabolized tilorone. This was associated with a dose-dependent decrease of bile formation and BSP excretion. Bile acid excretion was depressed as well. 4. BSP metabolism was not significantly affected by tilorone administration.

Animals↗

PubMed1977

[Tilorone, a synthetic immunostimulator possessing antitumor activity].

The authors report the results of studies on antitumor, immunostimulating and interieron-inducing properties of diethylamine fluorene derivative--tiloron, synthesized at Odessa laboratories of IGIC of the Ukrainian SSR Academy of Sciences by the originally elaborated method. It was found that tiloron does not suppress leucopoiesis, stimulates a number of protective reactions of the organism, including the factors of humoral and cell immunity, especially manifested under immunosuppression. Tiloron is shown to possess the definite antitumor activity being retained in peroral administration of the drug. Tiloron used together with cytostatic agents results in enhanced suppression of experimental tumors growth. Antitumor and immunostimulating action of tiloron on the experimental patterns under study is believed by the authors to be somewhat related with its interieron-inducing ability.

Animals↗

PubMedDate not supplied

Depression of the hepatic cytochrome P-450 mono-oxygenase system by administered tilorone (2,7-bis(2-(diethylamino)ethoxy)fluoren-9-one dihydrochloride).

The oral administration of the antiviral agent, tilorone-HCl (50 mg/day for 4 days) to rats caused losses of hepatic microsomal ethylmorphine N-demethylase, benzo(a)pyrene hydroxylase and aniline hydroxylase activities of 50, 44 and 22%, respectively. Microsomal levels of cytochrome P-450 and NADPH-cytochrome c reductase were lowered by 40 and 20% respectively, but levels of cytochrome b5 and NADH-cytochrome c reductase remained unchanged. After a single oral dose of tilorone-HCl (50 mg/kg) a loss of 38% of the microsomal cytochrome P-450 and 25% of the ethylmorphine N-demethylase activity was observed within 24 hr; recovery was complete within 8 to 10 days. Hexobarbital sleeping times and blood levels were elevated after tilorone administration (20 or 50 mg/kg/day for 4 days). In vitro, tilorone-HCl showed no inhibitory effect on microsomal drug metabolism nod did it affect the cytochrome P-450 content of the microsomes. The rate of incorporation of delta-amino(3H)levulinic acid into cytochrome P-450 was not affected by tilorone-HCl.

Aniline Hydroxylase↗

PubMed1992

Immunomodulation and drug acetylation: influence of the immunomodulator tilorone on hepatic, renal and blood N-acetyltransferase activity and on hepatic cytosolic acetyl coenzyme A content.

The biochemical alteration responsible for immunomodulator enhancement of drug acetylation in vivo was probed ex vivo and in vitro in the rat. Rat liver or kidney cytosol, obtained by differential centrifugation, or whole blood served as the source of N-acetyltransferase (NAT). Addition of tilorone (0.5-8.0 mM) to incubation mixtures containing procainamide (PA, 0.6 mM) and acetyl coenzyme A (AcCoA, 0.42 mM) resulted in the inhibition of N-acetylprocainamide formation, while lower concentrations of tilorone had no effect. Pretreatment of rats with tilorone (50 mg/kg) administered orally 48 hr prior to sacrifice did not alter hepatic apparent Km and Vmax for NAT toward PA compared to control animals. Utilization of an AcCoA regenerating system in the incubation mixtures also resulted in no significant differences in the apparent Michaelis-Menten parameters obtained. Acetylation activity in kidney and whole blood also was not altered by immunomodulator pretreatment. Hepatic cytosolic AcCoA content was reduced significantly 48 hr after tilorone pretreatment (5.10 +/- 2.1 vs 11.97 +/- 2.2 nmol/mg protein) (P less than 0.05). These data indicate that an increase in NAT content or activity is not the biochemical alteration responsible for immunomodulator enhancement of drug acetylation, and that the required cofactor, cytosolic AcCoA, is decreased by immunomodulator pretreatment.

Acetyl Coenzyme A↗

PubMed1978

Modulation of the acquisition and expression of immunity by Tilorone: II. Humoral responsiveness.

Tilorone (2,7-bis[(diethylamino)ethoxy]fluoren-9-one) can enhance the humoral immune response of mice to SRBC although Tilorone has no effect on functional activity of splenic B cells in the absence of immunogen. Tilorone does not alter the effective level of T cell help but does seem to alter the level of effective suppression. Tilorone seems to be an adjuvant only in the sense of removing a normal homeostatic control mechanism, perhaps suppressor T cells.

Adjuvants, Immunologic↗

PubMed1976

Experimental encephalitis caused by herpes simplex virus: comparison of treatment with tilorone hydrochloride and phosphonoacetic acid.

A mouse model of encephalitis caused by herpes simplex virus was used to compare the antiviral activity of tilorone hydrochloride with that of phosphonoacetic acid. These compounds were also administered simultaneously to determine whether the combination had a synergistic effect. Rates of survival and concentrations of virus in brain were used as criteria for judging the effectiveness of treatment. The fatal course of encephalitis was not altered by any treatment protocols in which tilorone hydrochloride was used alone. Four days of treatment with phosphonoacetic acid resulted in a long-term survival rate of about 15% of the infected, treated animals, and extension of this therapy for an additional three days resulted in an overall survival rate of about 35%. No increase in survival rate was obtained by use of phosphonoacetic acid and tilorone hydrochloride in combination. The concentration of virus in the brains of tilorone hydrochloride treated animals did not differ significantly from that in the untreated, infected control animals. Treatment with phosphonoacetic acid resulted in a reduction in titer of virus in brain and in an increased rate of survival.

Acetates↗

PubMed1979

Comparison of antiviral properties in mice of bis-pyrrolidinoacetamido-fluorenone (MLU-B75), bis-dipropylaminoacetamido-fluorenone (MLU-B76), and tilorone hydrochloride.

Like tilorone . HCl, its analogues, bis-pyrrolidinoacetamido-fluorenone (MLU-B75), and bis-dipropylaminoacetamido-fluorenone (MLU-B76), significantly protected mice against intraperitoneal challenge with a lethal dose of Mengo virus when administered prophylactically in a single oral dose of 250 mg per kg body weight. At lower doses the antiviral activity of MLU-B75 and MLU-B76 decreased more rapidly than that of tilorone. HCl. At the dose of 250 mg per kg the degree of antiviral protection and the titre of interferon induced by tilorone. HCl correlated well, but there was no correlation between the extent of protection and the detected amount of virus inhibitor induced by MLU-B76. It remains to be determined whether the antiviral protection elicited by the analogues of tilorone is mediated by interferon.

Animals↗

PubMed1977

Evaluation of various analogues of tilorone hydrochloride against Venezuelan equine encephalitis virus in mice.

The antiviral activity of tilorone hydrochloride and three of its analogues (11,002, 11,567, and 11,877) was assessed by oral and intraperitoneal (i.p.) administration to Venezuelan equine encephalitis (VEE) virus-infected mice. Significant increases in the percentage of survival (P < 0.01) were apparent after oral administration of tilorone and analogue 11,877 at dosages of 250 and 500 mg/kg. Neither tilorone nor 11,877 increased percentage of survival when dosages of 31.25 to 500 mg/kg were given by the i.p. route. Orally administered analogue 11,002 was effective against 100 mouse intracranial median lethal doses (MICLD(50)) of VEE virus at doses at 250 to 1,000 mg/kg; doses of 31.25 to 250 mg/kg given i.p. were effective against 10 MICLD(50). Oral dosages of 250 to 1,000 mg of analogue 11,567 per kg were active against 100 MICLD(50) of virus. By the i.p. route, 250 mg of 11,567 per kg protected mice against 1,000 MICLD(50), and a dose of 125 mg/kg protected against 100 MICLD(50). Oral treatment of VEE infection with analogue 11,567 24 h after subcutaneous inoculation of VEE virus resulted in no significant increase in the percentage of survivors. All survivors of these studies were susceptible to rechallenge 21 days after the first inoculation of virus.

Administration, Oral↗

PubMed1975

Effect of tilorone treatment on intracellular microbial infections in specific-pathogen-free mice.

Specific-pathogen-free CD-1 mice were treated orally with the drug tilorone (2,7-bis[2-diethylaminoethoxy]fluoren-9-one hydrochloride) at dosages of 10 or 100 mg per kg of body weight. Drug was given 24 h before challenge and then every other day for up to 15 days. Growth of sublethal doses of Listeria monocytogenes, Mycobacterium bovis (BCG Montreal), M. tuberculosis H37Rv, and Salmonella enteritidis in the livers and spleens of intravenously challenged mice was significantly increased compared with that in control animals receiving distilled water orally. Tilorone given every other day at a dosage of 10 mg/kg reduced (but did not completely ablate) the tuberculin response to the mycobacterial infections. Both tuberculin hypersensitivity and anti-mycobacterial resistance returned to normal values within days of stopping the drug treatment. Tilorone treatment at the 100-mg/kg dose level increased the growth of S. enteritidis in both intravenously and intragastrically challenged mice; this effect seemed to be due to the reduced ability of the host to express the normal granulomatous response to the microbial infection within the liver and spleen.

Animals↗