Skin radioprotection by 5-thio-D-glucose

The radioprotective effect of 5-thio-D-glucose on mouse skin was studied. Intraperitoneal injection of A/J mice with 1.5 g/kg of 5-thio-D-glucose 2 hr prior to X irradiation of the foot reduced early foot skin damage through Day 40 postirradiation by a dose modification factor of 1.3 +/- 0.1. Similarly, late foot deformity during Days 60-90 postirradiation was reduced by a factor of 1.2 +/- 0.1. The radioprotective effect of 5-thio-D-glucose was also compared with that of WR-2721, an aminothiol radioprotector, in CDF1 mice. An intraperitoneal injection of 1.5 g/kg of 5-thio-D-glucose reduced early radiation-induced skin damage by a dose modification factor of 1.2 +/- 0.1 as compared to that of 1.5 +/- 0.2 by 0.65 g/kg of WR-2721 in this strain of mice. 5-Thio-D-glucose is also known to specifically kill and radiosensitize hypoxic tumor cells. Consequently, this drug may be a useful radiotherapy adjuvant, reducing normal tissue damage and enhancing tumor control by minimizing hypoxic protection.     

Distribution of Adriamycin in mice bearing mammary adenocarcinoma 16/C

The response of solid mammary adenocarcinoma 16/C to treatment with Adriamycin is highly variable and ranges from growth under treatment to complete regression. Tumour and host factors were evaluated to determine the influence of each on the response. We determined that the concentration of Adriamycin in plasma and tumour was a function of tumour size and treatment history in mice bearing mammary adenocarcinoma 16/C. The plasma concentrations following a single dose of Adriamycin (10 mg/kg) increased in proportion to tumour mass without a concurrent increase in tumour concentration. When mice bearing large tumours (greater than 1.0 g) were treated with a multidose protocol, the plasma concentrations were higher and the tumour concentrations lower following the initial dose than following subsequent doses; in tumour-free mice, prior treatment with Adriamycin did not affect the plasma level achieved after a second dose. The magnitude of the decrease in plasma and increase in tumour concentrations was a function of the initial tumour size and the treatment schedule. The increase in tumour levels represented the sum of residual Adriamycin and drug bound as a result of the dose immediately prior to analysis. At the time of the initial treatment, the Adriamycin was distributed within each tumour in proportion to vascular perfusion. The percent of the tumour mass that was well-perfused appeared to increase with repeated treatments. The results indicate that the plasma concentration of Adriamycin did not necessarily reflect the tumour exposure in the mammary adenocarcinoma 16/C model. In hosts bearing mammary adenocarcinoma 16/C--or, possibly, other tumours that produce similar effects on the host--a low initial dose of Adriamycin might modify the distribution, possibly reduce the toxicity and allow escalation of subsequent doses with increased exposure of the tumour.     

Chronomodulatory effect of cyclosporine upon survival of DBA mice with L1210 leukemia

A circadian stage-dependent anti-tumor effect of cyclosporine was tested on 268 female DBA mice, 9-10 weeks of age. The mice were kept in 6 different environmental chambers on regimens of 12h of light alternating with 12h of darkness, staggered by 4h: they were inoculated intraperitoneally with 2 X 10(5) L1210 cells at one of 6 different circadian stages. At the same circadian stage, starting 48h after inoculation, for 4 days, each mouse received the vehicle, a fixed dose of cyclosporine (15 mg/kg b.w.), a varying dose of cyclosporine 5, 10, 20 and 25 mg/kg b.w.) or no treatment. Cyclosporine prolonged survival time in a circadian stage dependent fashion (p less than 0.01), as shown by an analysis of variance and by cosinor analysis (mesor = 8.45h; amplitude = 5.45h; acrophase = 12 HALO). Cyclosporine thus acts, in a feed-sideward, as a chronomodulator of the interaction between the tumor and its host.     

Histamine H1 receptors mediate the anorectic action of the pancreatic hormone amylin

We investigated the role of histamine H1 receptors in mediating the anorectic effect of intraperitoneally injected amylin (5 and 20 microg/kg), the amylin agonist salmon calcitonin (sCT; 10 microg/kg), leptin (1.3 mg/kg), and cholecystokinin (CCK; 20 microg/kg). The experiments were performed with mice lacking functional H1 receptors (H1Rko) and wild-type (WT) controls. The mice were also injected with the H3 antagonist thioperamide (20 mg/kg), which reduces feeding by enhancing the release of endogenous histamine through presynaptic H3 receptors. The feeding-suppressive effect of thioperamide was abolished in H1Rko mice. The anorectic effects of amylin and sCT were significantly reduced in 12-h food-deprived H1Rko mice compared with WT mice [1-h food intake: WT-NaCl 0.51 +/- 0.05 g vs. WT-amylin (5 microg/kg) 0.30 +/- 0.06 g (P < 0.01); H1Rko-NaCl 0.45 +/- 0.05 g vs. H1Rko-amylin 0.40 +/- 0.04 g; WT-NaCl 0.40 +/- 0.09 g vs. WT-sCT (10 microg/kg) 0.14 +/- 0.10 g (P < 0.05); H1Rko-NaCl 0.44 +/- 0.08 g vs. H1Rko-sCT 0.50 +/- 0.06 g]. The anorectic effect of leptin was absent in ad libitum-fed H1Rko mice, whereas CCK equally reduced feeding in WT and H1Rko animals. This suggests that the histaminergic system is involved in mediating the anorectic effects of peripheral amylin and sCT via histamine H1 receptors. The same applies to leptin but not to CCK. H1Rko mice showed significantly increased body weight gain compared with WT mice, supporting the role of endogenous histamine in the regulation of feeding and body weight.     

The effect of mass on the gastrointestinal absorption of plutonium and neptunium

Absorption and retention of plutonium were determined in mice after intragastric administration of either 6 X 10(-4) or 1.5 mg/kg in bicarbonate, citrate, or nitrate media. At the higher concentration, absorption of the citrate was greater than that of the nitrate; at the lower concentration, chemical form was not an important factor in absorption. Concentration and chemical form had much less influence on absorption by the neonatal (versus the adult) rat. The transfer factor (f1) for neonates was between one and two orders of magnitude higher than for adults. Absorption and retention of neptunium were determined in rats and/or mice after intragastric administration at doses ranging from 2.2 X 10(-7) to 43 mg/kg in nitrate solutions of pH 1.5. At the higher concentrations, absorption was 1.5 to 2.7%. For lower concentrations, absorption was 25 to 65 times less. In contrast to results obtained in adult animals, absorption of neptunium by neonates decreased with increasing dose. The data obtained in adult animals suggest that the f1 factor recommended by the ICRP for plutonium should be increased by a factor of 10, but the neptunium f1 factor, in contrast, should be decreased by a factor of 10.     

Difference in response to mouse hepatitis virus among susceptible mouse strains.

After intraperitoneal inoculation with a high-virulent mouse hepatitis virus (MHV) a significant difference was seen in survival time between DDD and CDF1 (BALB/c X DDD) mice, while 50% lethal doses were not significantly different. With 3 X 10(3) PFU of the virus CDF1 and DDD mice died in 45 and 120 hr, respectively, on the average. This difference of susceptibility between DDD and CDF1 mice was first demonstrable at the age of 1 week and was more pronounced at the age of 4 weeks but showed no dependence of the sex. Virus titers ran 2 to 3 log higher in the liver and blood of CDF1 than in those of DDD mice, while being only 1 log higher in the spleen. At an early stage of infection viral antigen was demonstrable by immunofluorescence in sinusoidal lining cells of the liver more prominently in VDF1 than in DDD mice. Interferon production occurring in parallel with virus growth was significantly higher in CDF1 than in DDD mice. In DDD mice, liver lesions were rather focal with some accumulation of round cells, while they were confluent with poor cellular response in CDF1 mice. Viral growth in cultured peritoneal macrophages from CDF1 mice was 1 log higher than in those from DDD mice. The results suggest that the divergence in response to MHV among susceptible mice greatly depends upon the susceptibility of macrophages and reticuloendothelial cells which constitute primary targets of the virus.     

Pharmacokinetic profile of 3beta-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,16-diene (VN/87-1), a potent androgen synthesis inhibitor, in mice

The objective of this study was to assess the pharmacokinetics and bioavailability of 3beta-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,16-diene (VN/87-1) in normal male mice and in SCID mice bearing human LNCaP tumor xenografts. VN/87-1 is a novel potent steroidal inhibitor of human testicular 17-alpha-hydroxylase/C(17,20)-lyase. The steroid also shows anti-androgenic activity and inhibits the growth of human prostate cancer cell lines (LNCaP) in vitro and in vivo. Male Balb/c mice were given a single oral, subcutaneous (s.c.) or intravenous (i.v.) bolus dose of VN/87-1 (25, 50 or 100 mg/kg). Male SCID mice bearing LNCaP tumor xenografts were injected with a single s.c. dose of VN/87-1 (50 mg/kg). The animals were sacrificed at various times up to 24 h after drug administration and blood was collected. The plasma samples were prepared and analyzed by a reversed phase HPLC system equipped with a diode array detector. A non-compartmental pharmacokinetic approach was used to evaluate the plasma level versus time data. Following i.v. administration of VN/87-1, the plasma levels declined exponentially with an elimination half-life of 1.2+/-0.03 h. The absolute bioavailability of the 50 mg/kg dose after oral or s.c. administration was 12.08+/-2 or 57.2+/-4.5%, respectively. VN/87-1 is a high clearance (5.0+/-1.3 l/h per kg) compound in mice and its volume of distribution was relatively large (6.5+/-1.2 l/kg). The pharmacokinetic parameters of VN/87-1 were not significantly altered in SCID mice bearing human LNCaP tumor xenografts. VN/87-1 is well absorbed from the subcutaneous site compared with absorption from the gastrointestinal tract and shows linear kinetics at doses up to 100 mg/kg.     

Neutrophil depletion does not prevent lung edema after endotoxin infusion in goats

Neutropenia was produced in goats by injection of either nitrogen mustard, (1.5 mg/kg) or hydroxyurea (200 mg X kg-1 X day-1). A nitrogen mustard (M + E) group (n = 6), a hydroxyurea (H + E) group (n = 5), and a control (E) group (n = 7) were given 1-h infusions of endotoxin (5 micrograms/kg total dose), then monitored for up to 5 h. Postmortem extravascular lung water (EVLW) was significantly higher in the M + E group (14.2 +/- 4.4 ml/kg) and the E group (11.9 +/- 3.9 ml/kg) when compared with a normal control (6.6 +/- 1.3 ml/kg) group that did not receive endotoxin. EVLW in a group made neutropenic with nitrogen mustard (6.7 +/- 1.3 ml/kg) and the H + E (7.9 +/- 1.5 ml/kg) groups were not statistically different from each other or from normal controls. Circulating neutrophil counts averaged 32 +/- 42 cells/microliter in the M + E group and 180 +/- 210 cells/microliter in the H + E group. Only minimal histological changes were seen in the H + E group, but the E and M + E lungs had severe pulmonary edema. We conclude that neutrophils are not required for increased EVLW and decreased arterial O2 partial pressure after endotoxin infusion, and hydroxyurea prevents at least part of the pulmonary edema after endotoxin by a mechanism that is not neutrophil dependent.     

Short-term immobilization of mice by methohexitone

The feasibility of short-term immobilization for <5 min of female mice by methohexitone sodium was studied. In C3H/Neu mice, methohexitone at a dose <40 mg/kg did not result in chemical restraint, doses >50 mg/kg caused considerable lethality. A dose of 44 mg/kg, applied intraperitoneally at a concentration of 6.46 mg/ml, is suitable for immobilization without complications. This concentration was chosen in order to achieve an injection volume of about 0.15 ml for a mouse with an average body weight of 22 g, corresponding to about 1 mg/mouse. Complete immobilization, defined as absence of the righting reflex, was observed within 3.3 +/- 0.8 min (mean +/- SD, n = 10) after the injection and lasted for 1.5 +/- 0.7 min. Recovery of the animals was complete after a total period of 10 to 15 min post-injection. No gross pathomorphological changes were induced when intraperitoneal injections of methohexitone were repeated 10 times within 10 days. In the present study, complete immobilization of the mice was safely achieved after 87 out of 90 injections. In conclusion, immobilization by intraperitoneal injection of methohexitone is a feasible and reliable method in the experimental studies of female mice.     

Metallothionein induction as a potent means of radiation protection in mice

A striking resistance to lethal damage from a single dose of 6-8 Gy of X rays has been found in mice which had received various pretreatments to induce metallothionein (MT) synthesis in the liver prior to irradiation. Mice were injected with manganese (10 mg Mn/kg) or cadmium (3 mg Cd/kg) salt subcutaneously, or a patch of dorsal skin (2 X 2 cm2) was excised 1 or 2 days prior to irradiation. The increased tolerance of these mice to radiation was established by a marked decrease of mortality rate, an increase of mean survival time, a reduction of weight loss, and a smaller decrease in the number of leukocytes as compared with the control group. The LD50/30 for control mice was 6.3 Gy, while the corresponding values for the groups pretreated with Mn, Cd, and skin excision were 7.5, 7.7, and 7.9 Gy, respectively. The normal level of MT in mouse liver was approximately 25 micrograms/g tissue. This level increased 2.5- to 3-fold 24 h after 6.3 Gy irradiation. The MT levels of mice pretreated with Cd, Mn, and skin excision were increased 8-, 5-, and 7-fold, respectively, prior to irradiation as compared with the preirradiation control. These results indicate that the induction of MT in mouse liver is a significant factor in the mechanism of protection against radiation.     

Presence of Kynurenic Acid in the Mammalian Brain

Kynurenic acid, a tryptophan metabolite able to antagonize the actions of the excitatory amino acids, has been identified and measured for the first time in the brain of mice, rats, guinea pigs, and humans by using an HPLC method. Its content was 5.8 +/- 0.9 in mouse brain, 17.8 +/- 2.0 in rat brain, 16.2 +/- 1.5 in guinea pig brain, 26.8 +/- 2.9 in rabbit brain, and 150 +/- 30 in human cortex (pmol/g wet wt. mean +/- SE). The regional distribution of this molecule was uneven. In rats, guinea pigs, and rabbits, the brainstem was the area richest in this compound. Tryptophan administration (100-300 mg/kg, i.p.) to rats resulted in a significant increase of the brain content of kynurenic acid. Similarly, 1 h after probenecid administration (200 mg/kg, i.p.), the brain content of kynurenate increased by fourfold, thus suggesting that its turnover rate is relatively fast.     

Long-term infusions of p-boronophenylalanine for boron neutron capture therapy: evaluation using rat brain tumor and spinal cord models

Rat 9L gliosarcoma cells infiltrating the normal brain have been shown previously to accumulate only approximately 30% as much boron as the intact tumor after administration of the boronated amino acid p-boronophenylalanine (BPA). Long-term i.v. infusions of BPA were shown previously to increase the boron content of these infiltrating tumor cells significantly. Experiments to determine whether this improved BPA distribution into infiltrating tumor cells after a long-term i.v. infusion improves tumor control after BNCT in this brain tumor model and whether it has any deleterious effects in the response of the rat spinal cord to BNCT are the subjects of the present report. BPA was administered in a fructose solution at a dose of 650 mg BPA/kg by single i.p. injection or by i.v. infusion for 2 h or 6 h, at 330 mg BPA/kg h(-1). At 1 h after the end of either the 2-h or the 6-h infusion, the CNS:blood (10)B partition ratio was 0.9:1. At 3 h after the single i.p. injection, the ratio was 0.6:1. After spinal cord irradiations, the ED(50) for myeloparesis was 14.7 +/- 0.4 Gy after i.p. administration of BPA and 12.9 +/- 0.3 Gy in rats irradiated after a 6-h i.v. infusion of BPA; these values were significantly different (P < 0.001). After irradiation with 100 kVp X rays, the ED(50) was 18.6 +/- 0.1 Gy. The boron compound biological effectiveness (CBE) factors calculated for the boron neutron capture dose component were 1.2 +/- 0.1 for the i.p. BPA administration protocol and 1.5 +/- 0.1 after irradiation using the 6-h i.v. BPA infusion protocol (P < 0.05). In the rat 9L gliosarcoma brain tumor model, the blood boron concentrations at 1 h after the end of the 2-h infusion (330 mg BPA/kg h(-1); n = 15) or after the 6-h infusion (190 mg BPA/kg h(-1); n = 13) were 18.9 +/- 2.2 microg 10B/g and 20.7 +/- 1.8 microg 10B/g, respectively. The irradiation times were adjusted individually, based on the preirradiation blood sample, to deliver a predicted 50% tumor control dose of 8.2 Gy ( approximately 30 photon-equivalent Gy) to all tumors. In the present study, the long-term survival was approximately 50% and was not significantly different between the 2-h and the 6-h infusion groups. The mode of BPA administration and the time between administration and irradiation influence the 10B partition ratio between the CNS and the blood, which in turn influences the measured CBE factor. These findings underline the need for clinical biodistribution studies to be carried out to establish 10B partition ratios as a key component in the evaluation of modified administration protocols involving BPA.     

Disruption of DNA synthesis and structure of mouse L1210 leukemia cells, sensitive and resistant to 1-methyl-1 nitrosourea and 1,3-bis(2-chloroethyl)-1-nitrosourea in vivo

Leukemia L1210 cells with acquired resistance to 1-methyl-1-nitrosourea (MNU) (L1210/MNU) and 1.3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (L1210/BCNU) were developed from leukemia L1210 cells sensitive to these drugs (L1210/0). The modal chromosome number of leukemia L1210/MNU and L1210/BCNU cells increases from 40 (L1210/0) to 41. It was shown that in leukemia L1210/MNU cells the inhibition of DNA synthesis after MNU administration in a therapeutic dose (80 mg/kg) is lasted within 24 hours, while that in leukemia L1210/0 cell--within 96 hours. After administration of BCNU (20 mg/kg) inhibition of DNA synthesis in leukemia L1210/BCNU cells reached of 50% of control in comparison with practically complete inhibition of DNA synthesis in leukemia L1210/0 cells. Centrifugation on alkaline sucrose density gradients revealed no differences in the rate of sedimentation of leukemia L1210/0, L1210/MNU and L1210/BCNU cell lysates. After 1 hour treatment with MNU of mice bearing L1210/MNU and L1210/0 leukemia cells single-strand breaks in DNA were determined. After 4 hours these strand-breaks retained in leukemia L1210/0 cells, but were eliminated in leukemia L1210/MNU cells. Administration of BCNU to mice with leukemia L1210/0 and L1210/BCNU cells resulted in both cases in the production of DNA aggregates. There is no complete cross-resistance between MNU and BCNU which allows a substitution of these drugs providing for the increase in their therapeutic efficiency.     

Treatment and survival study in the C57BL/6J-APC(Min)/+(Min) mouse with R-flurbiprofen

Our previous studies with the mouse model of familial adenomatous polyposis (FAP), C57BL/6J-APC(Min)/+ or Min mouse, demonstrated the optimal dose for adenoma reduction with R-flurbiprofen was 10 mg/kg/day as an undivided dose. Divided doses exhibited no increased efficaciousness. This study examines 10 mg/kg R-flurbiprofen daily (qd) on survival as well as a second daily (q.o.d.) schedule and compares it with sulindac sulfone. The q.o.d. schedule at 10 mg/kg was equally efficacious as qd treatment at the same dose. For the q.o.d. group, tumor number decreased similarly (p<0.01); while body weight gain (p<0.01), hematocrit and average tumor area (both, p<0.05) were improved compared with qd treatment. Treatment with R-flurbiprofen (10 mg/kg/day) increased survival significantly (p=0.0004, log-rank) compared to vehicle treated animals. Major biological endpoints (hematocrit, weight gain, tumor number, average and total area [99% reduction]) were significantly improved in treated animals (p<0.01). Sulindac sulfone treatment (50 mg/kg/day) of the Min mouse produced no significant biological benefit. The dose schedule study suggests that for tumor reduction it is necessary to attain a threshold drug-level but not necessarily sustain it over 24 hrs (pharmacodynamic t1/2 > pharmacokinetic t1/2). During the period of administration R-flurbiprofen dramatically prolongs survival for the mouse model of the human disease, FAP.     

Effects of iron deficiency and exercise on myoglobin in rats

The effects of iron deficiency and endurance training on muscle myoglobin (Mb), body weights, and blood lactic acid concentration were studied in rats. Fifty animals were divided into four groups: anemic trained (AT), normal trained (NT), anemic sedentary (AS), and normal sedentary (NS). Following 5 weeks of dietary control, the mean hemoglobin values for the AT and AS rats were 0.013 +/- 0.002 mmol X l-1 (8.7 +/- 1.4 g X dl-1) and 0.014 +/- 0.003 mmol X l-1 (9.2 +/- 1.7 g X dl-1) respectively, and did not significantly change throughout the study. AT and NT rats were run on a motor driven treadmill 4 days/week for 6 weeks up to a pre-established time of 90 min. Following the training, body weights of the AT (157 +/- 13 g) and NT (153 +/- 13 g) rats were lower than their respective sedentary groups AS (172 +/- 9 g) and NS (176 +/- 15 g). Resting blood lactic acid concentration following training was lower in both trained groups, AT (3.3 +/- 2.0 mM) and NT (2.3 +/- 1.9 mM) compared to AS (8.2 +/- 2.6 mM) and NS (3.8 +/- 1.6 mM). Training increased Mb concentration in hearts of both the anemic and normal trained groups (AT, 0.66 +/- 0.13 mg X g-1; NT, 0.95 +/- 0.08 mg X g-1) compared to the sedentary groups (AS, 0.44 +/- 0.08 mg X g-1; NS, 0.70 +/- 0.13 mg X g-1). Only the AT rats showed an increase in skeletal muscle Mb. This study provides evidence that myoglobin may limit aerobic metabolism.     

Protection by WR-3689 against gamma-ray-induced intestinal damage: comparative effect on clonogenic cell survival, mouse survival, and DNA damage

The aminophosphorothioate WR-3689 was characterized for its ability to protect mouse jejunal cells in vivo from single doses of X or gamma radiation. First, the effect of the drug on the survival of jejunal stem cells was examined using a clonogenic end point, the crypt microcolony assay. When WR-3689 was administered 30 min prior to whole-body irradiation, the number of surviving crypt cells was markedly increased at all doses of the drug, although protection began to level out at doses larger than 600 mg/kg. Protection was maximal when the drug was given 30 min before whole-body irradiation and declined rapidly with both shorter and longer intervals. Protection factors (PFs) were obtained by measuring survival curves for clonogenic crypt cells as a function of radiation dose; WR-3689 given 30 min before whole-body irradiation protected jejunum in the microcolony assay with a PF of 1.26 +/- 0.02, 1.50 +/- 0.10, and 1.65 +/- 0.10 at doses of 200, 400, and 800 mg/kg, respectively. Next, the effect of WR-3689 on the survival of jejunal stem cells was determined by assaying the survival of mice given X-ray doses to the whole abdomen in the range leading to death from the gastrointestinal syndrome. The PFs based on the LD50 values for 11-day survival were 1.31 +/- 0.05 (200 mg/kg) and 1.48 +/- 0.05 (400 mg/kg). Crypt-cell survival and animal survival were thus modified to a similar extent by this agent. Finally, the effect of WR-3689 on the induction of DNA single-strand breaks (SSBs) in jejunal cells was measured using an adaptation of the alkaline elution methodology. In mice treated with WR-3689 (400 or 800 mg/kg) 30 min prior to whole-body irradiation with 10 Gy there was no significant reduction in the number of DNA SSBs induced either in samples of the jejunum or in the cycling crypt cells, providing further evidence that there is no simple relationship between the modification of DNA SSBs and the survival of jejunal stem cells.     

Vildagliptin in drug-na?ve patients with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple-dose study.

This 24-week double-blind, randomized, multicenter, placebo-controlled, parallel-group study was performed in 632 drug-na?ve patients with type 2 diabetes to assess efficacy and tolerability of vildagliptin (50 mg qd, 50 mg bid, or 100 mg qd). HbA1c decreased modestly in patients receiving placebo (Delta=-0.3+/-0.1%) and to a significantly greater extent in patients receiving vildagliptin 50 mg qd (Delta=-0.8+/-0 .1%), 50 mg bid (Delta=-0.8+/-0.1%), or 100 mg qd (Delta=-0.9+/-0.1%, p<0.01 for all groups VS. placebo) from an average baseline of 8.4%. In patients diagnosed >or=3 months before enrollment, HbA1c increased with placebo (Delta=+0.2+/-0.2%) and between-treatment differences (vildagliptin-placebo) were -0.8+/-0.2% (p<0.001), -0.7+/-0.2% (p=0.003), and -0.9+/-0.2% (p<0.001) with vildagliptin 50 mg qd, 50 mg bid, and 100 mg qd, respectively. There was no apparent dose-response in the overall population; however, in patients with high baseline HbA1c, there were greater reductions with either 100 mg dose regimen (Delta=-1.3+/-0.2% and -1.4+/-0.2%) compared to 50 mg qd (Delta=-0.8+/-0.1%). Body weight decreased modestly in all groups (by 0.3 to 1.8 kg). The incidence of adverse events was similar across all groups and 相似文献   

Lymphocyte Hprt mutant frequency and sperm toxicity in C57BL/6 mice treated chronically with Azathioprine

Many patients undergoing chronic therapy with the purine analogue Azathioprine (Aza) have highly elevated HPRT lymphocyte mutant frequencies (MFs), and it is likely that these increases are due to selection of pre-existing HPRT mutant lymphocytes. A similar selection in germ cells might result in an increased frequency of the Lesch-Nyhan syndrome. In this study, a mouse model for Aza mutant selection was developed and Aza toxicity was evaluated in the germ cells of treated mice. Groups of 20 male C57BL/6 mice were treated by gavage three times/week with 0, 5, 10, 25, 50, or 100mg/kg Aza, and three to eight mice from each group were sacrificed at various times for up to 23 weeks. Mice treated with 25-100mg/kg Aza were all dead by 14 weeks of treatment. Hprt lymphocyte MF assays indicated that the treated mice had reduced numbers of spleen lymphocytes. Most treated mice had Hprt MFs similar to those of control mice (2.1+/-1.6 x 10(-6)), however, highly elevated MFs were detected in one out of three mice given 5mg/kg for 10 weeks, one out of three mice given 10mg/kg for 10 weeks, and one out of eight mice given 10mg/kg for 23 weeks (e.g., 233 x 10(-6) after 10 weeks of 5mg/kg). Sequence analysis of Hprt cDNA indicated that all mutant clones from one of these mice had a T-->A transversion in the initiation codon. Multiplex-PCR on mutant clones from the other two mice indicated that all the clones from one had a deletion of Hprt exons 2 and 3, while most of the mutants from the other had lost all of the Hprt exons. Measurements of testicular weight, and of sperm count, viability, morphology, and motility found that Aza produced low levels of toxicity in sperm, with the most consistent effect being a reduction in the testicular weight. The data suggest that mice chronically treated with 5 and 10mg/kg Aza (doses similar to those used in humans) have elevated Hprt MFs due to clonal amplification of selected Hprt mutants. The results also suggest that mice treated with these doses of Aza retain reasonable fertility, and will be useful for breeding experiments to examine the possibility of increasing the germ-line transmission of Hprt mutations.     

Comparative characteristics of the antitumor and immunodepressive activity of carminomycin on the L-1210 experimental model]

The antitumor activity of carminomycin was estimated by the number of lymphoma colonies formed in the spleen of DBA/2 mice on their inoculation with the bone marrow cells from mice with transplantable leukemia L-1210. The immunodepressive properties of carminomycin were determined by the number of the antibody forming cells in the spleen of CBA and DBA/2 mice with leukemia L-1210 after immunization with sheep red blood cells. It was found that in a single dose of 1.5 mg/kg carminomycin inhibited the lymphoma colonies by 50 per cent. The maximum immunodepressive effect was observed when carminomycin was used in a single dose of 1.5 mg/kg 48 hours after the antigen stimulation. In this case the number of the antibody forming cells in DBA/2 mice with leukemia L-1210 was lower than that in CBA mice without leukemia.     

Parthenolide has limited effects on nuclear factor-kappa beta increases and worsens survival in lipopolysaccharide-challenged C57BL/6J mice

Parthenolide, a sesquiterpene lactone, inhibited lipopolysaccharide (LPS) stimulated nuclear factor (NF)-kappabeta and cytokine production in vitro and in rats, and improved survival in LPS challenged Swiss albino mice. We investigated whether increased survival with parthenolide was associated directly with inhibition of NF-kappabeta and cytokines in LPS challenged C57BL/6J mice. In RAW 264.7 cells, parthenolide inhibited LPS-stimulated NF-kappabeta and cytokines (interleukin [IL]-1alpha, -1beta, -2, -4, -6, and -10, interferon-gamma, tumor necrosis factor-alpha, granulocyte macrophage-colony stimulating factor, migratory inhibitory protein-1 and -2alpha, JE, and RANTES). In mice (n = 366) receiving lethal intraperitoneal (i.p.) LPS (40 mg/kg), compared to placebo, each of 5 parthenolide doses (0.25 to 4 mg/kg i.p. following LPS) reduced survival at 168h and overall worsened the hazards ratio of survival (mean +/- S.E.M.) (1.29 +/- 0.12, p = 0.04). In other mice (241), compared to saline challenge, nonlethal LPS (2.5 mg/kg) increased NF-kappabeta in lung and kidney combined and 12 of 13 plasma cytokines early (1 and 3 h) and late (6, 9 and 12 h) (p < or = 0.002 for each). Compared to nonlethal LPS, lethal LPS increased NF-kappabeta and 12 of 13 cytokines early but not significantly and late significantly (p < or = 0.05 for each). With lethal LPS, compared to placebo, parthenolide (1 mg/kg) decreased NF-kappabeta and 10 of 13 cytokines early and increased NF-kappabeta and 11 of 13 cytokines late (p < or = 0.02 for early vs. late). Although parthenolide inhibits NF-kappabeta and cytokines in vitro, its effects on these mediators and survival in animal sepsis models vary. Theses differences must be understood before parthenolide or related agents are applied clinically for sepsis.