Amantadine decreases d-amphetamine stimulation and increases d-amphetamine anorexia in mice.

Amantadine hydrochloride (Symmetrel), an antiviral, antiparkinson agent that is most frequently used clinically at oral doses of 2 to 3 mg/kg, significantly decreased d-amphetamine-induced CNS stimulation (motor activity) and simultaneously increased d-amphetamine-induced anorexia (milk intake) in mice. Amantadine did this at oral doses of 2.5 and 5 mg/kg, which alone had no effect on either motor activity or milk intake.     

Antiviral Activity of a bis-Benzimidazole Against Experimental Rhinovirus Infections in Chimpanzees

The marked antiviral activity of (S,S-1,2-bis(5-methoxy-2-benzimidazolyl)-1,2-ethanediol (Abbott 36683) against rhinoviruses in tissue culture warranted investigation of its antiviral activity in vivo. Antiviral levels in mouse sera were attained with an oral dose as small as 10 mg/kg and detectable antiviral levels of drug were also found in lung, liver, kidney, intestinal contents, and urine of mice given a single 300 mg/kg oral dose. Antiviral serum levels were also obtained when monkeys were given a single oral dose of Abbott 36683. Six chimpanzees were infected with 100 median tissue culture infective dose units (TCID(50)) of rhinovirus 30. Three of the animals were treated with Abbott 36683, 100 mg/kg daily for 4 consecutive days. Virus shedding occurred in the infected controls but could not be demonstrated in the treated animals from postinfection days 1 to 8. Two of the treated animals did, however, shed virus on day 9. The compound was retested in chimpanzees at dosage levels of 15 and 50 mg/kg daily for 4 days. Each animal was challenged with 100 TCID(50) of rhinovirus 49. Partial protection was obtained. In a third trial, a single 100 mg/kg dose of the compound was administered to chimpanzees infected with rhinovirus 44. Virus was isolated from all throat smears taken from treated animals, indicating that at the lowest drug level no protection occurred.     

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.     

CYCLOSPORIN A INHIBITS THE IN VIVO PRODUCTION OF INTERLEUKIN-1β AND TUMOUR NECROSIS FACTOR α, BUT NOT INTERLEUKIN-6, BY A T-CELL-INDEPENDENT MECHANISM

The effect of cyclosporin A (CsA) on cytokine production in the tissue chamber model of acute inflammation was investigated. CsA caused a dose-related inhibition of interleukin 1β (IL-1β) production in both normal and athymic mice, confirming earlier conclusions that this effect is not T cell dependent (ED₅₀s 40 and 53 mg/kg p.o., respectively).Tumour necrosis factor alpha (TNF-α) levels were similarly affected with ED₅₀s of 40 and 58 mg/kg p.o. for normal and athymic mice, respectively. By contrast, CsA inhibited interleukin 6 (IL-6) production only in normal mice (ED₅₀27 mg/kg p.o.)Differences in the absolute production of the three cytokines in normal and athymic mice were also noted. IL-1β and IL-6 levels were two-fold higher in athymic mice, while for TNF-α, there was no difference between the two groups.The present findings support the authors' original hypothesis, that the inhibitory mechanism of CsA on IL-1β is not mediated via T cells. The same mechanism also seems responsible for the inhibition of TNF-α production, but not for IL-6, where inhibition by CsA appears to require the presence of T cells.     

Hypoglycemic effect of the total flavonoid fraction from Folium Eriobotryae

The antidiabetic effect of the total flavonoids fraction from leaves of Eriobotrya japonica (EJF) was evaluated through normal and streptozotocin-induced diabetic mice with graded oral doses of 150, 300, 450 mg/kg for 7 days or 14 days. The result showed that the dose of 300 mg/kg and 450 mg/kg resulted significant hypoglycemic effect on normal mice, the dose of 300 mg/kg induced significant decrease in plasma glucose concentration (PGC), glycosylated serum protein (GSP), total cholesterol (TC) and triglyceride (TG), and significant increase in superoxide dismutase (SOD) activity and serum insulin level in streptozotocin-diabetic mice. These results suggested that EJF has hypoglycemic potential.     

Immunomodulatory effect of Moringa oleifera Lam. extract on cyclophosphamide induced toxicity in mice

Immunomodulatory effect of ethanolic extract (50%) of M. oleifera leaves (MOE) has been studied in normal and immunosuppressed mice models. Different doses of MOE i.e. 125, 250 and 500 mg/kg body weight of mice were administered orally for 15 days. Cyclophosphamide at a dose of 30 mg/kg body weight was administered orally for the next 3 days. On day 16 and 19, hematological parameters like white blood cell (WBC) count, red blood cell (RBC) count, haemoglobin level (Hb), percent neutrophils and organ weight were recorded. Effect of MOE on phagocytic activity of mice macrophages was determined by carbon clearance test. MOE showed significant dose dependent increase in WBC, percent neutrophils, weight of thymus and spleen along with phagocytic index in normal and immunosuppressed mice. The results indicate that MOE significantly reduced cyclophosphamide induced immunosuppression by stimulating both cellular and humoral immunity.     

当归内酯对免疫抑制小鼠免疫功能的重建作用(英文)

探讨当归内酯(ASDL)对免疫抑制小鼠免疫功能的重构作用。通过小鼠腹腔注射环磷酰胺建立免疫抑制动物模型。采用免疫器官重量法和小鼠腹腔巨噬细胞吞噬鸡红细胞实验检测了ASDL对非特异性免疫功能的影响;用血清溶血素分光光度法检测了对体液免疫功能的作用;用MTT法进行了致分裂原诱导的小鼠脾淋巴细胞的增值反应实验,再用乳酸脱氢酶法测定了NK和CTL细胞活性,从而确定ASDL对小鼠细胞免疫功能的影响。结果表明:ASDL能够对免疫低下小鼠的非特性和特异性免疫功能起到一定的重构作用。但是这种效果并不是剂量依赖性的,20 mg/kg这个剂量的效果明显好于5和80 mg/kg这两个剂量。上述结果表明ASDL能够显著提高免疫低下小鼠的免疫功能。     

Biological characterization of 10-(2-propynyl) estr-4-ene-3, 17-dione (MDL 18,962), an enzyme-activated inhibitor of aromatase

MDL 18,962 was shown to be a highly specific, potent (Ki = 3-4 nM), enzyme-activated inhibitor of aromatase with minimal intrinsic endocrine properties. The affinity of MDL 18,962 was higher for human and baboon placental aromatase than for rhesus placental or rodent ovarian aromatase. These species differences necessitated the development of a novel model of peripheral aromatase utilizing human enzyme. Human choriocarcinoma trophoblast xenografts in athymic nude mice were used for pharmacologic and pharmacokinetic evaluation of MDL 18,962. The ED50 for inhibition of aromatase activity in these trophoblast tumors at 6 h post-treatment was 1.4 mg/kg, s.c. and 3.0 mg/kg, oral. Preliminary results indicated that the ED50 for inhibition of peripheral aromatization of androgen by MDL 18,962 in female baboons was 0.01 mg/kg, i.v. and 4 mg/kg, oral.     

T-cell-deficient mice display normal recovery from experimental rotavirus infection.

Rotaviruses are common causes of diarrhea in animals and humans. Little is known, however, about the components of the host response to these viruses. Rotavirus infection was studied in athymic mice experimentally infected with murine rotavirus. Neonatal T-cell-deficient mice experienced a self-limited gastrointestinal infection which was identical to that observed in age-matched immunocompetent mice. Adult T-cell-deficient seronegative mice and age-matched normal mice showed a similar extent of resistance to symptomatic rotavirus infection. In both cases, the infection was resolved without the generation of antirotavirus antibody. These studies indicate that host defense against murine rotavirus requires neither functional T-lymphocytes nor specific antiviral antibody.     

Protection against acetaminophen hepatotoxicity by clofibrate pretreatment: role of catalase induction

Mice pretreated with the peroxisome proliferator clofibrate (CFB) are highly resistant to acetaminophen (APAP)-induced hepatotoxicity. The objective of the present study was to investigate whether the increase in hepatic catalase activity following CFB pretreatment plays a role in this hepatoprotection. An irreversible inhibitor, 3-amino-1,2,4-triazole (3-AT), was used to modulate catalase activity. Hepatic catalase activity in mice pretreated with CFB (500 mg/kg, i.p., for 10 days) was significantly inhibited by 3-AT (100 or 500 mg/kg, i.p.). In addition, the lower dose of 3-AT (100 mg/kg) had minimal effect on biliary and urinary excretion of APAP metabolites generated from a nontoxic dose, suggesting that APAP metabolism was not modulated by this dose of 3-AT. The mortality rate of corn-oil-pretreated mice challenged with APAP (800 mg/kg, p.o.) was significantly increased by 3-AT (100 mg/kg, i.p.) given 1 h before APAP. As expected, CFB pretreatment conferred full protection against APAP-induced hepatotoxicity. The same 3-AT treatment, however, did not abolish hepatoprotection in CFB-pretreated mice, despite the marked inhibition of hepatic catalase activity. In conclusion, these results indicate that elevated catalase activity in mice exposed to CFB does not appear to mediate the hepatoprotection, suggesting that other cellular defense mechanisms are involved.     

Bone marrow cell chromosomal aberrations and styrene biotransformation in mice given styrene on a repeated oral schedule

Styrene's capacity to induce chromosomal aberrations was studied in bone marrow cells of CD1 male mice. No mutagenic effect could be detected after either a 4-day treatment course with daily oral doses of 500 mg/kg or a 70-day course with daily oral doses of 200 mg/kg. Urinary elimination of styrene metabolites related to styrene-7,8-oxide formation (i.e. phenylethylene glycol, mandelic acid, benzoic acid, phenylglyoxylic acid and total mercapturic acids) was quantitatively evaluated in the group of mice given the 200 mg/kg dose. In parallel, kinetic studies were made on styrene and styrene-7,8-oxide blood concentrations in the same group of animals. These determinations were carried out on days 1 and 70 of treatment by spectrophotometric, gas chromatographic and mass fragmentographic procedures.Not even nanograms of styrene-7,8-oxide were found in the blood of styrene-treated mice. This suggests that the metabolite does not migrate from the cellular compartment where it is formed being immediately metabolized or irreversibly bound to cellular structures.This observation could well explain the lack of mutagenic effects observed.     

Synergistic anti-inflammatory interaction between meloxicam and aminoguanidine hydrochloride in carrageenan-induced acute inflammation in rats

Interaction studies with inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) inhibitor have been conducted to assess the nature of interaction and the possible therapeutic advantage. The interaction between meloxicam--a selective COX-2 inhibitor--and aminoguanidine hydrochloride--a selective iNOS inhibitor-- was examined in carrageenan-induced paw edema in rats. Appropriate statistical method was applied to detect the nature of anti-inflammatory interaction. Different doses of meloxicam (1, 3, 10 and 30 mg/kg) or aminoguanidine hydrochloride (10, 30, 100 and 300 mg/kg) were administered orally to adult male albino rats. Higher doses of meloxicam (3, 10 and 30 mg/kg) showed statistically significant anti-inflammatory effect. However, aminoguanidine hydrochloride did not show any anti-inflammatory activity. Combination of sub-threshold dose of meloxicam (1 mg/kg) with increasing doses of aminoguanidine hydrochloride (30, 100 and 300 mg/kg) resulted in synergistic anti-inflammatory effect. Combined therapy with sub-threshold dose of aminoguanidine hydrochloride (30 mg/kg) with increasing doses of meloxicam (1, 3, 10 and 30 mg/kg) also resulted in synergistic anti-inflammatory effect. The possible mechanism of interaction could be the stimulation of COX-2 activity by nitric oxide (NO) by combining with heme component. These results suggest that co-administration of meloxicam and aminoguanidine hydrochloride may be an alternative in clinical control of inflammation.     

Eradication of a large MOPC-315 tumor in athymic nude mice by chemoimmunotherapy with Lyt2+ splenic T cells from melphalan-treated BALB/c mice bearing a large MOPC-315 tumor

Summary We have previously shown that spleen cells from BALB/c mice that are in the process of eradicating a large MOPC-315 tumor following low-dose (2.5 mg/kg) melphalan (l-phenylalanine mustard) therapy are effective in preventing tumor progression upon adoptive transfer into BALB/c mice bearing a barely palpable tumor that had been treated with a subcurative dose of melphalan [Mokyr et al. (1989) Cancer Res 49: 4597]. Here we show that such spleen cells in conjunction with a subcurative dose of drug (adoptive chemoimmunotherapy, ACIT) can cause the complete regression of a large (15–20 mm) s.c. MOPC-315 tumor in a large percentage of T-cell-deficient (athymic nude) tumor-bearing mice. Spleen cells that were effective in ACIT of athymic nude mice displayed in vitro a substantial direct lytic activity against MOPC-315 tumor cells, and the lytic activity was greatly enhanced when the spleen cells were cultured for 5 days with or without mitomycin-C-treated MOPC-315 stimulator tumor cells. The cells responsible for the therapeutic effectiveness of the spleen cells in ACIT of athymic nude mice, as well as the cells responsible for the direct in vitro anti-MOPC-315 lytic activity of the spleen cells, were of the Lyt 2 and not the L3T4 phenotype. Most of the athymic nude mice that completely eradicated a large MOPC-315 tumor as a consequence of ACIT were capable of rejecting a challenge with 30–100 times the minimal lethal tumor dose for 100% of normal BALB/c mice administered more than 1 month after the ACIT. The ability of these athymic nude mice to resist the tumor challenge was associated with the presence of a greatly elevated percentage of cells expressing T cell surface markers in their spleens. Thus, it is conceivable that splenic Lyt 2⁺ T cells from melphalan-treated BALB/c mice bearing a large MOPC-315 tumor mediate their therapeutic effectiveness in ACIT of athymic nude mice bearing a large MOPC-315 tumor, at least in part, through direct cytotoxicity for MOPC-315 tumor cells. In addition, eradication of a large MOPC-315 tumor through cooperation between antitumor immunity and melphalan toxicity endues the athymic nude mice with an elevated percentage of T cells in their secondary lymphoid organs, and these T cells are probably responsible for the long-lasting protective antitumor immunity exhibited by these mice.Supported by research grant IM-435A from the American Cancer Society and research grant B-8806 from the Bane EstateIn partial fulfillment of the requirements for the Doctor of Philosophy DegreeRecipient of Career Development Award CA-01350 from the National Cancer Institute     

Influence of Dose and Route of Administration on the Enantioselective Pharmacokinetics of TJ0711 Hydrochloride in Rats

The enantioselective pharmacokinetics of TJ0711 hydrochloride were studied in rats given different doses of rac‐TJ0711 hydrochloride via intravenous and oral routes. R‐ and S‐TJ0711 hydrochloride were both rapidly absorbed, and the average AUC_0‐∞ of R‐TJ0711 hydrochloride was greater than that of S‐TJ0711 hydrochloride after intragastric administration, with an R/S AUC ratio 1.11 and 1.35 for 30 and 50 mg/kg dose group, respectively. In contrast, the average AUC_0‐∞ of R‐TJ0711 hydrochloride was smaller than that of S‐TJ0711 hydrochloride after intravenous injection, with an R/S AUC ratio 0.57 and 0.73 for 10 and 20 mg/kg dose group, respectively. R‐TJ0711 hydrochloride plasma half‐lives were shorter than those of S‐TJ0711 hydrochloride for all groups. AUC_0‐4h and C_max between the two enantiomers were significantly different after oral administration of 50 mg/kg dose of the racemate, while no significant differences between the two enantiomers were found for all the pharmacokinetic parameters of the 30 mg/kg dose group. Significant differences between the two enantiomers were detected for nearly all the pharmacokinetic parameters after intravenous administration, except for the V_Z of 20 mg/kg dose group. This study suggests that dose and route of administration will influence the enantioselectivity in the pharmacokinetics of TJ0711 hydrochloride in rats. Chirality 27:53–57, 2015. © 2014 Wiley Periodicals, Inc.     

Verapamil contributes to the clastogenic effects of acrylamide, cyclophosphamide, and dioxidine on somatic cells of BALB/C and C57BL/6 mice

The chromosome aberration assay of metaphase bone marrow cells was used to study the clastogenic effects of acrylamide, cyclophosphamide, dioxidine, and their combinations with Verapamil (a calcium antagonist) in male BALB/C and C57BL/6 mice. Verapamil gavage at single (5 mg/kg) and repeated doses (2.5 and 5 mg/kg five times at 24-h intervals) significantly enhanced the clastogenic activity of acrylamide (50 and 100 mg/kg intraperitoneally) in BALB/C mice; in C57BL/6 mice, this effect was only observed when they received Verapamil at doses of 2.5 mg/kg for 5 days. Verapamil administered repeatedly (2.5–10 mg, gavage) significantly increased the clastogenic activity of cyclophosphamide (10 mg/kg intraperitoneally) in C57BL/6 mice. In BALB/C mice, this effect of Verapamil was only observed at a dose of 10 mg/kg (gavage). When injected intraperitoneally at a single dose of 0.1–0.4 mg/kg, Verapamil significantly enhanced the clastogenic activity of cyclophosphamide in mice of both strains. This calcium antagonist produced identical effects when administered to BALB/C mice intraperitoneally (2.5 and 5 mg/kg) and by gavage (5 mg/kg) and to C57BL/6 mice intraperitoneally (5 and 10 mg/kg) and by gavage (2.5 mg/kg). Repeated administration of Verapamil (at all doses tested) promoted the clastogenic effect of dioxidine (100 mg/kg intraperitoneally) on C57BL/6 mice, having no such influence on BALB/C mice. These results demonstrate the co-clastogenic activity of Verapamil in mice and suggest that its specific manifestations depend on the dose, method, and route of drug administration and the genotype of test animals.     

Verapamil contributes to the clastogenic effects of acrylamide, cyclophosphamide, and dioxidine on somatic cells of BALB/C and C57BL/6 mice

The chromosome aberration assay of metaphase bone marrow cells was used to study the clastogenic effects of acrylamide, cyclophosphamide, dioxidine, and their combinations with Verapamil (a calcium antagonist) in male BALB/C and C57BL/6 mice. Verapamil gavage at single (5 mg/kg) and repeated doses (2.5 and 5 mg/kg five times at 24-h intervals) significantly enhanced the clastogenic activity of acrylamide (50 and 100 mg/kg intraperitoneally) in BALB/C mice; in C57BL/6 mice, this effect was only observed when they received Verapamil at doses of 2.5 mg/kg for 5 days. Verapamil administered repeatedly (2.5-10 mg, gavage) significantly increased the clastogenic activity of cyclophosphamide (10 mg/kg intraperitoneally) in C57BL/6 mice. In BALB/C mice, this effect of Verapamil was only observed at a dose of 10 mg/kg (gavage). When injected intraperitoneally at a single dose of 0.1-0.4 mg/kg, Verapamil significantly enhanced the clastogenic activity of cyclophosphamide in mice of both strains. This calcium antagonist produced identical effects when administered to BALB/C mice intraperitoneally (2.5 and 5 mg/kg) and by gavage (5 mg/kg) and to C57BL/6 mice intraperitoneally (5 and 10 mg/kg) and by gavage (2.5 mg/kg). Repeated administration of Verapamil (at all doses tested) promoted the clastogenic effect of dioxidine (100 mg/kg intraperitoneally) on C57BL/6 mice, having no such influence on BALB/C mice. These results demonstrate the co-clastogenic activity of Verapamil in mice and suggest that its specific manifestations depend on the dose, method, and route of drug administration and the genotype of test animals.     

Effect of supplemental magnesium on the kidney levels of cadmium, zinc, and copper of mice exposed to toxic levels of cadmium

In this report, we present the results of our investigations on the effect of Mg pretreatment on Cd and bioelements (Cu and Zn) contents in kidney of mice exposed to acute and subacute Cd intoxication. Acute intoxication was performed on male Swiss mice given a single oral dose of 20 mg Cd/kg body weight and mice given the same dose of Cd but pretreated with 40 mg Mg/kg body weight. For subacute intoxication one group of mice was given 10 mg Cd/kg body weight every day, for 2 wk, and the other one received the same dose of Cd after oral Mg intake of 20 mg/kg body weight. Cd, Cu, and Zn content was determined in kidney by atomic absorption spectrophotometry. In acute Cd intoxication, Mg pretreatment resulted in significant decrease of Cd in kidney after 4 and 6 h, compared with animals given only Cd. Under the condition of subacute Cd intoxication, Mg supplementation reduced Cd kidney content after 2 wk for about 30%, compared with animals treated with Cd only. The effect of Mg on Cu and Zn kidney content was also beneficial.     

Ibogaine reduces amphetamine-induced locomotor stimulation in C57BL/6By mice, but stimulates locomotor activity in rats.

The effect of ibogaine hydrochloride on locomotor stimulation induced by d-amphetamine sulfate was tested in male C57BL/6By mice and in female Sprague-Dawley rats. In mice, locomotor stimulation induced by d-amphetamine at 1 or 5 mg/kg s.c. was reduced by prior administration of one or two injections of ibogaine (40 mg/kg), given 2 or 18 hours earlier. This reduction in locomotor activity persisted for two days. Locomotor stimulation induced by a higher dose (10 mg/kg) of d-amphetamine was not reduced by such prior administration of ibogaine. A lower dose of ibogaine (20 mg/kg) did not reduce the subsequent locomotor activity induced by d-amphetamine. Ibogaine decreased striatal dopamine levels, while d-amphetamine increased them. Ibogaine treatment (2 x 40 mg/kg, 18 hours apart) induced a decrease by 30% in the level of striatal dopamine and its metabolites measured in tissue extracts 3 hours after the second ibogaine injection. One hour after d-amphetamine (5 mg/kg) administration, the level of striatal dopamine increased by 26%. Although the level of striatal dopamine was initially lower in the ibogaine-pretreated mice, d-amphetamine (5 mg/kg) administration induced an increase in striatal dopamine and its metabolites. The effect of ibogaine seems to be species specific, since in rats pretreated with ibogaine 18 hours before d-amphetamine, locomotor stimulation induced by d-amphetamine was further increased. In addition, the in vitro electrical-evoked release of [3H]dopamine from striatal tissue was either unchanged or inhibited in the presence of d-amphetamine, and after ibogaine pretreatment in vivo, the release of tritium in the presence of d-amphetamine was inhibited or stimulated in mice and rats, respectively.     

Visual Cycle Modulation as an Approach toward Preservation of Retinal Integrity

Increased exposure to blue or visible light, fluctuations in oxygen tension, and the excessive accumulation of toxic retinoid byproducts places a tremendous amount of stress on the retina. Reduction of visual chromophore biosynthesis may be an effective method to reduce the impact of these stressors and preserve retinal integrity. A class of non-retinoid, small molecule compounds that target key proteins of the visual cycle have been developed. The first candidate in this class of compounds, referred to as visual cycle modulators, is emixustat hydrochloride (emixustat). Here, we describe the effects of emixustat, an inhibitor of the visual cycle isomerase (RPE65), on visual cycle function and preservation of retinal integrity in animal models. Emixustat potently inhibited isomerase activity in vitro (IC₅₀ = 4.4 nM) and was found to reduce the production of visual chromophore (11-cis retinal) in wild-type mice following a single oral dose (ED₅₀ = 0.18 mg/kg). Measure of drug effect on the retina by electroretinography revealed a dose-dependent slowing of rod photoreceptor recovery (ED₅₀ = 0.21 mg/kg) that was consistent with the pattern of visual chromophore reduction. In albino mice, emixustat was shown to be effective in preventing photoreceptor cell death caused by intense light exposure. Pre-treatment with a single dose of emixustat (0.3 mg/kg) provided a ~50% protective effect against light-induced photoreceptor cell loss, while higher doses (1–3 mg/kg) were nearly 100% effective. In Abca4-/- mice, an animal model of excessive lipofuscin and retinoid toxin (A2E) accumulation, chronic (3 month) emixustat treatment markedly reduced lipofuscin autofluorescence and reduced A2E levels by ~60% (ED₅₀ = 0.47 mg/kg). Finally, in the retinopathy of prematurity rodent model, treatment with emixustat during the period of ischemia and reperfusion injury produced a ~30% reduction in retinal neovascularization (ED₅₀ = 0.46mg/kg). These data demonstrate the ability of emixustat to modulate visual cycle activity and reduce pathology associated with various biochemical and environmental stressors in animal models. Other attributes of emixustat, such as oral bioavailability and target specificity make it an attractive candidate for clinical development in the treatment of retinal disease.     

Effect of tilorone hydrochloride on graft-versus-host (GvH) reaction in mice.

The effects of tilorone hydrochloride (TH), a powerful interferonogenic agent exhibiting also immune modulatory properties, on GvH reaction was studied, using the popliteal lymph node assay in mice. Administration of TH at ten days 0 or +2 relative to cell transfer to recipient mice led to a significant dose-dependent reduction of GvH reaction, whereas treatment of prospective donor mice at day -4 or -2 induced an enhanced GvH re activity of donor spleen cells. This effect was found not to be due to an altered proportion in the spleen cell inoculum of B and T lymphocytes, which latter are responsible for induction for GvH reaction. However, since normal parental lymphocytes are prepared for an enhanced GvH reactivity by addition of TH-treated macrophages, a stimulatory effect of the latter cells via macrophage-derived mediators, induced by TH, is suggested.