Significant Dose-related Trend Research Articles

Reproductive and neurobehavioral effects of dinotefuran in an F1 -generation toxicity study in mice.

Few studies were found for neurobehavioral toxicity of dinotefuran in mammals. This study was designed to evaluate the reproductive and neurobehavioral effects of dinotefuran exposure in mice. Dinotefuran was given in the diet to provide levels of 0% (control), 0.015%, 0.03%, and 0.06% from 5 weeks of age of the F0 generation to 11 weeks of age of the F1 generation in mice. Selected reproductive and neurobehavioral parameters were measured. Movement time increased with a significant dose-related trend, and the related variables of rearing time decreased in significant dose-related trends in adult males in the F0 generation. Litter size and weight increased in significant dose-related trends, and sex ratio decreased in a significant dose-related trend. The average body weight of offspring increased in a significant dose-related trend on postnatal day (PND) 21 in both sexes. In the olfactory orientation on PND 14 in female offspring, the time required lengthened in a significant dose-related trend. In male offspring, total distance and the average speed decreased in significant dose-related trends, and the average time of rearing, number of defecations, and frequencies of mice with urination increased in a significant dose-related trend. In female offspring, the related variables of rearing increased in significant dose-related trends. In spontaneous behavior of males, the parallel lines during the control and treatment groups indicated a significant distance in the number of horizontal activities. The dose levels of dinotefuran in the present study produced several adverse effects on reproductive and neurobehavioral parameters in mice.

Pharmacokinetics and Safety of the Nucleoside Analog Antiviral Drug Galidesivir Administered to Healthy Adult Subjects.

Galidesivir (BCX4430) is an adenosine nucleoside analog broadly active in cell culture against multiple RNA virus families, and active in animal models of viral diseases associated with Ebola, Marburg, yellow fever, Zika, and Rift Valley fever. Current studies demonstrated the pharmacokinetics and safety of the first-in-human evaluations of galidesivir as intramuscular (IM) and intravenous (IV) formulations. Two double-blind, placebo-controlled, dose-ranging studies were conducted enrolling 126 healthy subjects. Study 1 evaluated the safety and tolerability of IM galidesivir over single day dosing, single day dosing ± lidocaine, and 7-day dosing with lidocaine. Study 2 evaluated the safety and tolerability of single ascending doses of IV galidesivir. Safety and tolerability were evaluated via clinical and laboratory monitoring. The plasma concentration-time profile of galidesivir at doses 0.3 to 10mg/kg IM was characterized by rapid absorption, an initial rapid distribution and clearance phase, and an extended terminal elimination phase. The initial rapid distribution and extended terminal elimination were mimicked in the profile of galidesivir at doses 5 to 20mg/kg IV. No fatal events or related serious adverse events were reported. No clinically significant dose-related trends in laboratory values, vital signs, electrocardiograms, or echocardiograms were noted. Galidesivir was safe and generally well tolerated.

YM150, an Oral Direct Factor Xa Inhibitor, as Prophylaxis for Venous Thromboembolism in Patients with Elective Primary Hip Replacement Surgery. A Dose Escalation Study.

Activated factor X (FXa) is a pivotal blood coagulation factor positioned at the crossroads of the extrinsic and intrinsic coagulation cascade. Inhibitors of FXa are anticoagulants that could be used in the prevention and treatment of thrombosis and venous thromboembolism (VTE). YM150 is a once daily, orally active FXa inhibitor. A randomized, enoxaparin-controlled, dose escalation study was performed in 174 patients undergoing elective primary hip replacement surgery to assess safety and efficacy of 7–10 days treatment with oral doses of YM150 (3, 10, 30 or 60 mg once daily starting 6–10 h after surgery) or s.c. enoxaparin (40 mg once daily starting 12 h before surgery). Safety is defined as major and/or clinically relevant non-major bleeding, and efficacy as venous thromboembolism detected by mandatory bilateral venography on the last treatment day and/or symptomatic VTE. The study was open-label with blinded evaluation of all outcomes by an independent Adjudication Committee. There were no major bleeds. Three clinically relevant non-major bleeds were reported, 1 (2.9%; 95% CI: 0–16%) in the 3 mg and 2 (5.7%; 1–19%) in the 10 mg YM150 dose groups. No trend was observed in the incidence of minor bleeds with dose of YM150 in the range 10 mg to 60 mg daily. The proportion of patients with minor bleeding events in the enoxaparin group (22%; 95% CI: 10–39%) was similar to that in the YM150, 60 mg daily group (24%; 11–41%). 147 patients (84%) were considered to have an evaluable venogram. The incidences of VTE were 52% (95% CI: 31–72%), 39% (22–57%), 23% (9–40%), and 19% (7–37%) for the respective 3, 10, 30 and 60 mg YM150 once daily dose groups in comparison with 39% (22–57%) for enoxaparin. Logistic regression analysis revealed a statistically significant dose-related trend (p=0.006) for patients reaching the VTE endpoint during YM150 treatment. No trend in any of the measured safety parameters was observed with study treatment (YM150 or enoxaparin) or dose of YM150. Oral, once daily doses of YM150, 10 mg to 60 mg administered 6 to 10 h after primary hip replacement, were shown to be safe, well tolerated and effective in this study.

Combined effects of maternal exposure to fungicides on behavioral development in F1 -generation mice: 2. Fixed-dose study of thiabendazole.

Few published studies are reported for the neurobehavioral toxicity of combined exposure to fungicides in mammals. This study was aimed to re-evaluate the reproductive and neurobehavioral effects of maternal exposure to combined imazalil (IMZ) and thiabendazole (TBZ) with fixed-dose of TBZ in mice. IMZ/TBZ were given in the diet to provide levels of 0%/0% (control), 0.0015%/0.018% (IMZ/TBZ), 0.006%/0.018% and 0.024%/0.018% during the gestation and lactation periods. Selected reproductive and neurobehavioral parameters were measured in the F1 generation. No adverse effect of IMZ/TBZ was observed in litter size, litter weight, or sex ratio at birth. Concerning behavioral developmental parameters, the cliff avoidance on PND 7 of male offspring was restrained significantly in the treatment groups in a dose-related manner. Exploratory behavior examination indicated that the average time of rearing significantly lengthened in the high-dose group of male offspring. After weaning, the average time of rearing in exploratory behavior lengthened in a significant dose-related trend in adult females of the F1 generation. Spontaneous behavior examination indicated that the average speed decreased significantly through 120 min in the high-dose group of the F1 -generation males. In females, the average time of rearing lengthened significantly through 120 min in the high-dose group. In the longitudinal patterns, the parallel lines of the control and treatment groups indicated a significant distance in the average time of rearing in the F1 -generation females. The results from two combined exposure studies of IMZ/TBZ suggest that TBZ concentrations have caused major effects on exploratory and spontaneous behavior.

Reproductive and neurobehavioral effects of maternal exposure to ethiprole in F1 -generation mice.

Few published studies are reported for neurobehavioral toxicity of the phenylpyrazole insecticide ethiprole in mammals. This study was designed to evaluate the reproductive and neurobehavioral effects of maternal exposure to ethiprole in mice. Ethiprole was given in the diet to provide levels of 0 (control), 0.0002, 0.001, and 0.005% during the gestation and lactation periods. Selected reproductive and neurobehavioral parameters were measured in the F1 generation. No adverse effect of ethiprole was observed in litter size, litter weight, or sex ratio at birth. The average body weight of male and female offspring was increased significantly in treatment groups at postnatal day (PND) 21. With respect to behavioral developmental parameters, the time of olfactory orientation on PND 14 of male offspring was accelerated significantly in the high-dose group. For movement activity of exploratory behavior of female offspring in the F1 generation, number of horizontal activities increased significantly in the high-dose group and the average speed declined significantly in all treatment groups. After weaning, the rearing time and the average time of rearing lengthened in a significant dose-related trend in adult males and females of the F1 generation. Spontaneous behavior examination indicated that total distance and rearing time increased in the high-dose group, and number of horizontal activities and movement time decreased in a significant dose-related trend through 120 min in the F1 -generation females. The high-dose level of ethiprole in the present study produced several adverse effects in neurobehavioral parameters after weaning without administration in mice.

Reproductive and Neurobehavioral Effects of Ethiprole Administered to Mice in the Diet.

Few studies were found for neurobehavioral toxicity of the phenylpyrazole insecticide ethiprole in mammals. This study was designed to evaluate the reproductive and neurobehavioral effects of ethiprole exposure in mice. Ethiprole was given in the diet to provide levels of 0 (control), 0.0003, 0.0009, and 0.0027% from 5 weeks of age of the F0 generation to 11 weeks of age of the F1 generation in mice. Selected reproductive and neurobehavioral parameters were measured. Movement time increased with a significant dose-related trend, and frequencies of mice with urination increased in the high-dose group of adult males in the F0 generation. The average body weight of male and female offspring increased significantly in treatment groups at postnatal days (PNDs) 7, 14, and 21. Surface righting on PND 7 of male offspring was accelerated in a significant dose-related trend. In female offspring, olfactory orientation on PND 14 was accelerated significantly on the route of higher-dose groups, and time of all treatment groups. Total distance, movement time, average speed, and average time of movement significantly decreased, and frequencies of mice with urination increased in a significant dose-related trend in male offspring in the F1 generation. Longitudinal patterns of spontaneous behavior differed in the number of horizontal activities, movement time, and average speed in treatment groups in males. The number of horizontal activities of females decreased in a significant dose-related trend through 120 min. The dose levels of ethiprole in the present study produced several adverse effects in neurobehavioral parameters in mice. Birth Defects Research 109:1568-1585, 2017. © 2017 Wiley Periodicals, Inc.

Dolutegravir in antiretroviral-naive adults with HIV-1

Objective:To evaluate the efficacy and safety/tolerability of dolutegravir (DTG, S/GSK1349572), a potent inhibitor of HIV integrase, through the full 96 weeks of the SPRING-1 study.Design:ING112276 (SPRING-1) was a 96-week, randomized, partially blinded, phase IIb dose-ranging study.Methods:Treatment-naive adults with HIV received DTG 10, 25, or 50 mg once daily or efavirenz (EFV) 600 mg once daily (control arm) combined with investigator-selected dual nucleos(t)ide reverse transcriptase inhibitor backbone regimen (tenofovir/emtricitabine or abacavir/lamivudine). The primary endpoint of the study was the proportion of participants with plasma HIV-1 RNA less than 50 copies/ml, based on time to loss of virologic response at 16 weeks (conducted for the purpose of phase III dose selection), with a planned analysis at 96 weeks. Safety and tolerability were also assessed.Results:Of 208 participants randomized to treatment, 205 received study drug. At week 96, the proportion of participants achieving plasma HIV-1 RNA less than 50 copies/ml was 79, 78, and 88% for DTG 10, 25, and 50 mg, respectively, compared with 72% for EFV. The median increase from baseline in CD4+ cells was 338 cells/μl with DTG (all treatment groups combined) compared with 301 cells/μl with EFV (P = 0.155). No clinically significant dose-related trends in adverse events were observed, and fewer participants who received DTG withdrew because of adverse events (3%) compared with EFV (10%).Conclusion:Throughout the 96 weeks of the SPRING-1 study, DTG demonstrated sustained efficacy and favorable safety/tolerability in treatment-naive individuals with HIV-1.

Inhibitors of the Platelet Thrombin Receptor

Not that long ago, aspirin, heparin, and warfarin were the only available antithrombotic agents for treating cardiovascular disease patients at risk of thrombotic events. These agents are still used in several places around the world, and it is remarkable how difficult it was to discover other agents that are more effective and/or safer. Since the mid-1980s we have been witnessing an explosion of research on new antithrombotic therapies, resulting in the availability of ticlopidine and clopidogrel (thienopyridine P2Y12-receptor inhibitors), low–molecular-weight heparins (eg, enoxaparin), and intravenous GPIIb/IIIa-receptor inhibitors (abciximab, eptifibatide, and tirofiban), later followed by fondaparinux (a synthetic indirect intravenous anti-Xa agent), bivalirudin (an intravenous direct anti-IIa agent), and more recently, prasugrel (a more potent thienopyridine) (Figure). Figure. The coagulation cascade, platelet activation pathways, and targets of antithrombotic agents. inhib indicates inhibition; LMWH, low–molecular-weight heparin; AT, antithrombin; vWF, von Willebrandt factor; TxA2, thromboxane A2; and ADP, adenosine diphosphate. Articles see pp 1843 and 1854 In the near future, several new oral antithrombotic agents may become available for treating patients with cardiovascular diseases: ticagrelor (the first direct reversible P2Y12 antagonist), dabigatran (an oral direct anti-IIa agent), rivaroxaban (an oral direct anti-Xa agent), and apixaban (also an oral direct anti-Xa agent). Other P2Y12 antagonists (eg, elinogrel) and oral anti-Xa agents (edoxaban, betrixaban, YM150, and TAK-442) are being studied or will be studied in phase-III programs (Figure). New antiplatelet therapies that target pathways not affected by aspirin or P2Y12-receptor antagonists could provide more comprehensive inhibition of platelet activation, and contribute to a greater inhibition of platelet-mediated thrombosis. Inhibition of protease-activated receptor-1 (PAR-1), a receptor for thrombin, is a new attractive approach in the development of better and safer antiplatelet therapy. As shown in the Figure, thrombin is the key effector of the coagulation cascade, but is also …

Final Safety Assessment of Coal Tar as Used in Cosmetics

Coal Tar is a semisolid by-product obtained in the destructive distillation of bituminous coal, which functions in cosmetic products as a cosmetic biocide and denaturant--antidandruff agent is also listed as a function, but this is considered an over-the-counter (OTC) drug use. Coal Tar is a nearly black, viscous liquid, heavier than water, with a naphthalene-like odor and a sharp burning taste, produced in cooking ovens as a by-product in the manufacture of coke. Crude Coal Tar is composed of 48% hydrocarbons, 42% carbon, and 10% water. In 2002, Coal Tar was reported to the Food and Drug Administration (FDA) to be used in four formulations, all of which appear to be OTC drug products. Coal Tar is monographed by the FDA as Category I (safe and effective) OTC drug ingredient for use in the treatment of dandruff, seborrhoea, and psoriasis. Coal Tar is absorbed through the skin of animals and humans and is systemically distributed. In short-term studies, mice fed a diet containing Coal Tar found it unpalatable, but no adverse effects were reported other than weight loss; rats injected with Coal Tar experienced malaise in one study and decreased water intake and increased liver weights in another; rabbits injected with Coal Tar residue experienced eating avoidance, respiratory difficulty, sneezing, and weight loss. In a subchronic neurotoxicity study using mice, a mixture of phenols, cresols, and xylenols at concentrations approximately equal to those expected in Coal Tar extracts produced regionally selective effects, with a rank order of corpus striatum > cerebellum > cerebral cortex. Coal Tar applied to the backs of guinea pigs increases epidermal thickness. Painting female rabbits with tar decreases the absolute and relative weights of the ovaries and decreased the number of interstitial cells in the ovary. Four therapeutic Coal Tar preparations used in the treatment of psoriasis were mutagenic in the Ames assay. Urine and blood from patients treated with Coal Tar were genotoxic in bacterial assays. Coal Tar was genotoxic in a mammalian genotoxicity assay and induced DNA adducts in various tissue types. Chronic exposure of mice to Coal Tar significantly decreased survival and liver neoplasms were seen in a significant dose-related trend; in other studies using mice lung tumors and perianal skin cancers were found. Coal Tar was comedogenic in three small clinical studies. Folliculitis is associated with the prolonged use of some tars. Several published reports describe cases of contact sensitivity to Coal Tar. Polycyclic aromatic hydrocarbons, which make up Coal Tar, are photosensitizers and cause phototoxicity by an oxygen-dependent mechanism. A retrospective study of the reproductive toxicity of Coal Tar in humans compared exposed women to controls and found little difference in spontaneous abortion and congenital disorders. Cancer epidemiology studies of patients who have received Coal Tar therapy of one form or other have failed to link treatment with an increase in the risk of cancer. Although the Cosmetic Ingredient Review (CIR) Expert Panel believes that Coal Tar use as an antidandruff ingredient in OTC drug preparations is adequately addressed by the FDA regulations, the Panel also believes that the appropriate concentration of use of Coal Tar in cosmetic formulations should be that level that does not have a biological effect in the user. Additional data needed to make a safety assessment include product types in which Coal Tar is used (other than as an OTC drug ingredient), use concentrations, and the maximum concentration that does not induce a biological effect in users.

Once Daily YM150, an Oral Direct Factor Xa Inhibitor, for Prevention of Venous Thromboembolism in Patients Undergoing Elective Primary Hip Replacement.

YM150 is an orally active direct FXa inhibitor in clinical development. Proof of concept of YM150 was previously obtained in a dose escalation study, demonstrating a statistically significant dose-related trend in VTE prevention in patients undergoing total hip replacement (ONYX; J Thromb Haemost 2007; 5:1660–5). The present study with YM150 is a double blind, parallel, multi-center dose finding study in patients undergoing elective primary hip replacement surgery, with open label enoxaparin as control. Patients were randomly treated with 5, 10, 30, 60 or 120 mg YM150 once daily orally or 40 mg enoxaparin once daily subcutaneously. Patients were treated in hospital for approximately 1–2 weeks followed by home treatment for another 4 weeks, for in total 33–38 treatment days (prolonged treatment for hip replacements according to guidelines of Am. College of Chest Physicians (Geerts et al. Chest 2004: 126;338–400)). The administration of YM150 started 6–10 h after surgery, while treatment with enoxaparin started 12 ± 2 h before surgery. Mandatory bilateral venography was performed after 7–10 days of treatment. Follow up visits were performed at 2 and 4 weeks during home treatment, and 2, 4, and 8 weeks after end of study treatment. The sample size was estimated to be 960 randomized patients in order to yield 110 patients per treatment group with an evaluable venogram. The primary efficacy endpoint was defined as deep vein thrombosis, and/or symptomatic VTE and/or death, and primary safety endpoint as the incidence of major bleeding during the first 7–10 days of study treatment. Secondary efficacy endpoints were proximal and distal DVT (during the first 7–10 days) and symptomatic VTE during home treatment, and follow up. Secondary safety endpoints were the incidences of major, clinically relevant non-major (CRNM) and minor bleeding during the three study periods. Independent Adjudication Committees reviewed all venograms, bleeding reports, symptomatic VTEs, and deaths unaware of treatment allocation. An independent DSMB monitored the data to ensure the safety of the patients. 1017 patients were randomized from 81 sites in 17 European countries. Preliminary data showed that DVT was detected in 149 out of 727 evaluable venograms, one patient had symptomatic VTE, and one patient died (myocardial infarction) during the hospital treatment period. This results in a total primary efficacy outcome rate of 20.7% (151/729) in the evaluable study population, with a corresponding rate of major bleeding of 0.6% (6/1017). The breakdown of the results according to treatment group will be presented.

Transplacental carcinogenicity of 3′‐azido‐3′‐deoxythymidine in B6C3F1 mice and F344 rats

The prophylactic use of zidovudine (3'-azido-3'-deoxythymidine, AZT) during pregnancy greatly reduces transmission of HIV-1 from infected mothers to their infants; however, the affinity of host cell DNA polymerases for AZT also allows for its incorporation into host cell DNA, predisposing to cancer development. To expand upon previous transplacental carcinogenesis assays performed in CD-1 mice, the transplacental carcinogenicity of AZT was evaluated in a second mouse strain and a second rodent species. Date-mated female mice and rats were gavaged daily with 0, 80, 240, or 480 mg AZT/kg bw during the last 7 days of gestation. At 2 years postpartum, male and female B6C3F1 mouse and F344 rat offspring (n = 44-46 of each sex and species/treatment group) were necropsied for gross and microscopic tissue examinations. Under the conditions of these two-year studies, there was clear evidence of carcinogenic activity based upon significant dose-related trends and increases in the incidences of hemangiosarcoma in male mice and mononuclear cell leukemia in female rats. There was some evidence of carcinogenic activity in the livers of male mice based upon a positive trend and an increased incidence of hepatic carcinoma in the high-dose AZT group. The incidence of gliomas in female rats exceeded the historical background rates for gliomas in F344 rats. P53 overexpression was detected in some AZT-treated mouse neoplasms. These and other cancer-related findings confirm and extend those of previous transplacental carcinogenicity studies of AZT in mice, support the need for long-term follow-up of nucleoside reverse transcriptase inhibitor (NRTI)-exposed children, and indicate the necessity for effective protective strategies against NRTI-induced side effects.

Lifelong exposure to di-(2-ethylhexyl)-phthalate induces tumors in liver and testes of Sprague?Dawley rats

The plasticizer di-(2-ethylhexyl)-phthalate (DEHP) is the most important phthalate with respect to its production, use and occurrence in the environment. In standard carcinogenicity experiments with F344 rats and B6C3F1 mice, DEHP has been shown to induce hepatocellular tumors. Moreover, DEHP is strongly suspected to be a developmental and reproductive toxicant. The present study aimed at determining the long-term toxic effects of lifetime exposure to low concentrations of DEHP in Sprague-Dawley rat strain. Seven hundred and thirty male rats, stratified into four groups, received DEHP with the diet, resulting in dosages of 300, 95, 30 and 0 mg/kg per day for up to 159 weeks and were only sacrificed when moribund. All organs of the dead and sacrificed animals were histopathologically examined. Significantly increased tumor incidences after exposure to 300 mg/kg per day DEHP (P = 0.04 for testes and 0.05 for liver) and a significant dose-related trend (P(Trend) = 0.02 for testes and 0.03 for liver) were detected in both organs liver and testes. Time to tumor analysis revealed that DEHP-induced testicular tumors developed earlier in lifetime than hepatocellular neoplasias, and their multiplicity increased with time. In addition, animals exposed to the highest DEHP dose showed a significantly increased rate of testicular tubular atrophy (P < 0.01). In conclusion, this study shows for the first time that the rat testes are a target organ of DEHP carcinogenicity in Sprague-Dawley rats upon lifetime exposure. This new finding indicates the importance of evaluating the effects of lifetime exposure in assessing the potential human health risks of DEHP. In addition, the carcinogenicity should be evaluated in rat strains with low spontaneous tumor incidence in the organs known as target of DEHP toxicity.

Methoxychlor-Induced Alterations in the Histological Expression of Angiogenic Factors in Pituitary and Uterus

Within the reproductive system, oestrogenic stimulation of uterine and pituitary tissue typically causes a proliferative response accompanied by an angiogenic induction of new blood vessels from existing ones, thereby providing nutrients and oxygen to the growing tissue. The pro-oestrogenic pesticide methoxychlor (MXC), however, has shown a differential effect on proliferative activity. An increase in uterine growth is present, while the pituitary undergoes a decrease in size, even though the effect is accompanied by a characteristic oestrogen-induced elevation in pituitary prolactin concentration. The focus of the current study was whether the observed differences in tissue growth between uterus and pituitary in response to MXC administration were paralleled by a corresponding disparity in the expression of those growth factors (members of the vascular endothelial growth factor (VEGF) and angiopoietin families and their receptors) that are involved in the angiogenic cascade. Ovariectomized adult Sprague-Dawley female rats were administered MXC (0-200 mg/kg, oral) for 1 or 3 weeks. Immunohistochemical staining of uteri and pituitaries was performed under strictly controlled conditions for VEGF and its receptor VEGFR2, Angiopoietin-1 (Ang1) and angiopoietin-2 and their tyrosine kinase receptor Tie2, and platelet endothelial adhesion factor (as an index of vascularity). Image acquisition and densitometric assessments of staining intensity were conducted under blind conditions. The results showed uterine MXC-induced increases in the expression of VEGFR2 and Ang1, changes consistent with a normal proliferative response to oestrogenic stimulation. For VEGF, staining tended to be most pronounced in the stromal region, although there did not appear to be a progressive increase with dose. VEGFR2 expression showed significant dose-related trends in luminal and glandular epithelia by 1 week. Similar effects at 1 week were evident for Ang1 in glandular epithelium. In the anterior pituitary, a dose-related increase in VEGF was present for the 1 and 3 week treatments, and the number of pituitary vessels per unit area was also increased after 3 weeks. The effects indicate that even though the insecticide has not been found to cause an augmentation in pituitary growth, a dose-related rise in the expression of at least one principal angiogenic factor is present that may be associated with an increase in vascular density.

Recombinant LH in Support of Recombinant FSH in Female Hypogonadotropic Hypogonadism—Evidence of Threshold Effect

Recombinant LH in Support of Recombinant FSH in Female Hypogonadotropic Hypogonadism—Evidence of Threshold Effect

Weighted p‐Value Adjustments for Animal Carcinogenicity Trend Test

A typical animal carcinogenicity experiment routinely analyzes approximately 10-30 tumor sites. Comparisons of tumor responses between dosed and control groups and dose-related trend tests are often evaluated for each individual tumor site/type separately. p-Value adjustment approaches have been proposed for controlling the overall Type I error rate or familywise error rate (FWE). However, these adjustments often result in reducing the power to detect a dose effect. This paper proposes using weighted adjustments by assuming that each tumor can be classified as either class A or class B based on prior considerations. The tumors in class A, which are considered as more critical endpoints, are given less adjustment. Two weighted methods of adjustments are presented, the weighted p adjustment and weighted alpha adjustment. A Monte Carlo simulation shows that both weighted adjustments control the FWE well. Furthermore, the power increases if a treatment-dependent tumor is analyzed as in class A tumors and the power decreases if it is analyzed as in class B tumors. A data set from a National Toxicology Program (NTP) 2-year animal carcinogenicity experiment with 13 tumor types/sites observed in male mice was analyzed using the proposed methods. The modified poly-3 test was used to test for increased carcinogenicity since it has been adopted by the NTP as a standard test for a dose-related trend. The unweighted adjustment analysis concluded that there was no statistically significant dose-related trend. Using the Food and Drug Administration classification scheme for the weighted adjustment analyses, two rare tumors (with background rates of 1% or less) were analyzed as class A tumors and 11 common tumors (with background rates higher than 1%) as class B. Both weighted analyses showed a significant dose-related trend for one rare tumor.

Effects of Fumonisin B1on the Immune System of Sprague–Dawley Rats Following a 14-Day Oral (Gavage) Exposure

The effects of fumonisin B1(FB1) on the immune system of Sprague–Dawley rats were investigated. Groups of male and female rats (10 rats/group) were gavaged daily for 14 days with doses of 0, 5, 15, and 25 mg/kg body wt/day and the primary (IgM) response to sheep red blood cells expressed as plaque-forming cell numbers/106spleen mononuclear leukocytes (PFC/106splenocytes) and PFC/spleen was determined. There was a significant dose-related linear trend toward decreased PFC/106splenocytes (p= 0.003) and PFC/spleen cells (p= 0.001) in the male rats. Body weights, expressed as a percentage of the control, were significantly reduced (p= 0.002) in the male rats administered 15 and 25 mg/kg doses. The PFC numbers in female rats were not affected significantly by treatment (p> 0.05). For the remaining immunotoxicity studies, groups of male rats (10 rats/group) were gavaged with FB1doses of 0, 1, 5, and 15 mg/kg body wt/day for 14 days. There was a weakly significant dose-related trend toward increased numbers of serum immunoglobulin class G (p= 0.04). Also a significant dose-related increase (p= 0.013) inListeria monocytogenesnumbers was observed in the spleen at 24 hr postinfection. Treatment did not have a significant effect on organ weights, hematology, mitogen-induced lymphocyte transformation, calcium mobilization, the numbers of leukocytes and T-lymphocyte subsets, the natural killer cell activity, and phagocytosis (p≥ 0.05). These observations suggested that FB1may have indirect consequences for human health and warrant further investigations.

Effects of Fumonisin B1 on the Immune System of Sprague-Dawley Rats Following a 14-Day Oral (Gavage) Exposure

The effects of fumonisin B1 (FB1) on the immune system of Sprague-Dawley rats were investigated. Groups of male and female rats (10 rats/group) were gavaged daily for 14 days with doses of 0, 5, 15, and 25 mg/kg body wt/day and the primary (IgM) response to sheep red blood cells expressed as plaque-forming cell numbers/10(6) spleen mononuclear leukocytes (PFC/10(6) splenocytes) and PFC/spleen was determined. There was a significant dose-related linear trend toward decreased PFC/10(6) splenocytes (p = 0.003) and PFC/spleen cells (p = 0.001) in the male rats. Body weights, expressed as a percentage of the control, were significantly reduced (p = 0.002) in the male rats administered 15 and 25 mg/kg doses. The PFC numbers in female rats were not affected significantly by treatment (p > 0.05). For the remaining immunotoxicity studies, groups of male rats (10 rats/group) were gavaged with FB1 doses of 0, 1, 5, and 15 mg/kg body wt/day for 14 days. There was a weakly significant dose-related trend toward increased numbers of serum immunoglobulin class G (p = 0.04). Also a significant dose-related increase (p = 0.013) in Listeria monocytogenes numbers was observed in the spleen at 24 hr postinfection. Treatment did not have a significant effect on organ weights, hematology, mitogen-induced lymphocyte transformation, calcium mobilization, the numbers of leukocytes and T-lymphocyte subsets, the natural killer cell activity, and phagocytosis (p >/= 0. 05). These observations suggested that FB1 may have indirect consequences for human health and warrant further investigations.

1227 Dose-response trial across four oral doses of dolasetron (DM) for emesis prevention after moderately emetogenic chemotherapy (CT)

This double-blind multicenter trial studied four oral doses of OM for antiemetic effectiveness in 319 predominately CT-naive cancer patients, receiving IV CT. Patients were randomized to one of four treatments: 25, 50, 100, or 200 mg of DM, 30 minutes prior to CT with doxorubicin (in combination: 25–75 mg/m2 or alone: ≥ 40 mg/m2) and/or cyclophosphamide (500–1200 mg/m2). Efficacy was compared across doses using complete response (CR: no emetic episodes [EE] and no escape medication [EM]); CR + major response (CMR: 1–2 EE and no EM); patients assessment of nausea < 5 mm = no nausea) and satisfaction with antiemetic therapy via a 100 mm visual analog scale (VAS). At 24 hours, statistically significant linear trends (P < 0.0001) were detected across the 25, 50, 100, and 200 mg doses of DM, respectively, for CR (31%, 34%, 49%, and 46%), for CMR (28%, 43%, 52%, 56%), and for CR + no nausea (20.5%, 26.5%, 37.5%, 39.7%). Lineartrends with dose were also statistically significant for patient assessment of nausea (P < 0.0006) and general satisfaction (P < 0.0009). No significant dose related trends in the incidence of headache or elevated transaminases were detected. Single oral doses of DM are effective in preventing emesis in cancer patients with excellent safety and efficacy recorded with both the 100 and 200 mg doses of dolasetron. This double-blind multicenter trial studied four oral doses of OM for antiemetic effectiveness in 319 predominately CT-naive cancer patients, receiving IV CT. Patients were randomized to one of four treatments: 25, 50, 100, or 200 mg of DM, 30 minutes prior to CT with doxorubicin (in combination: 25–75 mg/m2 or alone: ≥ 40 mg/m2) and/or cyclophosphamide (500–1200 mg/m2). Efficacy was compared across doses using complete response (CR: no emetic episodes [EE] and no escape medication [EM]); CR + major response (CMR: 1–2 EE and no EM); patients assessment of nausea < 5 mm = no nausea) and satisfaction with antiemetic therapy via a 100 mm visual analog scale (VAS). At 24 hours, statistically significant linear trends (P < 0.0001) were detected across the 25, 50, 100, and 200 mg doses of DM, respectively, for CR (31%, 34%, 49%, and 46%), for CMR (28%, 43%, 52%, 56%), and for CR + no nausea (20.5%, 26.5%, 37.5%, 39.7%). Lineartrends with dose were also statistically significant for patient assessment of nausea (P < 0.0006) and general satisfaction (P < 0.0009). No significant dose related trends in the incidence of headache or elevated transaminases were detected. Single oral doses of DM are effective in preventing emesis in cancer patients with excellent safety and efficacy recorded with both the 100 and 200 mg doses of dolasetron.

Carcinogenicity study of 3,3′-dimethylbenzidine dihydrochloride in BALB/c mice

BALB/c mice (120/sex/dose) were given 0, 5, 9, 18, 35, 70 or 140 ppm of 3,3′-dimethylbenzidine dihydrochloride in their drinking-water and killed after 13, 26, 39, 52, 78 or 116 wk. Full histopathological evaluations were performed on all animals that were found dead or moribund, or that were killed on schedule. Fatal lung alveolar cell neoplasms began to appear in males receiving 140 ppm at 78 wk and there was a significant dose-related decrease in the time-to-death from this cause. There were no significant dose-related trends for this neoplasm in females, nor were there treatment-related effects on body weight, water consumption or other lesions in either sex. This is the first report of a neoplastic response to 3,3′-dimethylbenzidine dihydrochloride in mice.

The effects of moderate physical activity on menstrual cycle patterns in adolescence: Implications for breast cancer prevention

Girls who engage in strenuous physical activity are often amenorrheic and have recently been reported to be at a reduced risk of breast cancer. To determine whether moderate amounts of exercise affect menstrual cycle patterns and ovulatory frequency in young postmenarcheal girls, the menstrual cycles and physical activity patterns of 168 high school girls were monitored for a 6 month period. Anovulatory cycles were associated with later age at menarche, fewer elapsed years since menarche and greater levels of energy expended per week in physical activity. After adjusting for age at menarche and years since menarche, there was a significant dose-related trend in the risk of anovular menstrual cycles associated with increasing levels of physical activity (1-sided P = 0.03). Major determinants of average cycle length were weekly average energy expenditure (less than or equal to 750 kcal wk-1 associated with cycles that were on average 2.4 days longer), age at menarche (an increase of 0.7 days per year of age) and race (Asians having cycles about 1.9 days longer than Caucasians). Because a major determinant of breast cancer risk may be the cumulative number of ovulatory cycles, these data suggest that regular participation in moderate physical activity, by reducing the frequency of ovulatory cycles in adolescence, may provide an opportunity for the primary prevention of breast cancer.