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Biomedical subjects

G M Williams

Publications and source records attributed to G M Williams.

At least 109 records · Page 6Linked to original sources
PubMed1998

Five year impact of chemotherapy on morbidity attributable to Schistosoma japonicum infection in the Dongting Lake region.

OBJECTIVE: To determine changes in the last 5 years of the fraction of acute and chronic symptoms attributable to schistosomiasis japonica in fishing communities with moderate endemicity in the Dongting Lake region of China. METHOD: Complete medical histories, physical examinations, and stool samples were obtained from 1909 individuals (53% male) ranging in age from 4 to 81 years. Age, sex, occupation, frequency of water contact, number of times treated for schistosomiasis, and last year of treatment were tested as potential effect modifiers and confounders. RESULTS: Overall, there were very few infected cases and very little variation in any prevalence ratio with infection intensity, sex, age, year of last treatment, number of times treated or frequency of water contact. The attributable fraction of liver enlargement in one village was estimated at 0.114 (11.4%), although this was not significantly > 0(95% CI; -0.008-0.237). CONCLUSION: The chemotherapy-based schistosomiasis control programme in this locality has succeeded in reducing attributable morbidity to undetectable levels, but many uncertainties remain about sustaining control efforts in the future. Both old and new control strategies will have to be examined if the health and well-being of these people are to be maintained into the next millennium, given that periodic chemotherapy will not be accepted indefinitely.

Adolescent↗
PubMed1998

Epidemiological identification of Chinese individuals putatively susceptible or insusceptible to Schistosoma japonicum: a prelude to immunogenetic study of human resistance to Asian schistosomiasis.

An epidemiological method, field-tested in Hunan, China, to identify residents potentially susceptible or insusceptible to endemic schistosomiasis japonica is described, as a prelude to selection of subjects for immunogenetic studies. After an initial cross-sectional survey on two islands (Qingshan and Niangashan--population 2990) in 1995-1996, an informative cohort (N = 249) was selected for treatment and 9-month follow-up to measure exposure and re-infection. Both the population prevalence (15.8%) and the geometric mean intensity of infection (26.2 eggs/g faces) indicated that the islands were moderately endemic for schistosomiasis. Exposure measurements revealed a strong, positive, linear association (r = 0.70) between daily activity diaries and direct water-contact observation. Individuals identified as stool-positive for schistosomiasis had significantly more water contact than those who were egg-negative (P = 0.03). Almost all (93%) of the cohort had ultrasonographic evidence of periportal fibrosis before treatment but in only 1.2% was this fibrosis scored > 1 in terms of the stages identified by the World Health Organization. At the follow-up it was possible to classify the 249 subjects into three, distinct, exposure-infection epidemiological groups. The first group (N = 20) was susceptible to re-infection and constituted 8% of the cohort. The second group (N = 61) was apparently insusceptible to re-infection despite the continuing high levels of exposure and included 24% of the cohort. The other 68% of the cohort (N = 168) remained uninfected but were at most only moderately exposed, or had a status indeterminate due to non-compliance. This epidemiological identification of susceptibles and insusceptibles for schistosomiasis japonica' links field and ongoing laboratory studies aimed at characterising the genetic and immunological factors associated with resistance to re-infection and/or disease.

Adolescent↗
PubMed1998

The impact of domestic violence on women's mental health.

This longitudinal study aimed to establish a firmer scientific basis for recognition and treatment of post-traumatic psychiatric morbidity associated with domestic violence. The study used a sample of 335 women (mean age 45.5 years) recruited from the Royal Brisbane Hospital Emergency Department. This paper reports baseline data. The outcome measures of lifetime psychiatric diagnoses (DSM-111-R classification), showed that women who reported lifetime adult intimate abuse (n = 162) received significantly more diagnoses of generalised anxiety, dysthymia, depression, phobias, current harmful alcohol consumption and psychoactive drug dependence than those who reported no abuse ever (n = 173). Of the 191 women tested for lifetime post-traumatic stress disorder, those who reported lifetime abuse (n = 115) received significantly more diagnoses than those who reported no abuse (n = 76). Crude prevalence rates of psychiatric diagnoses for women who reported double abuse as child and adult were significantly higher than for women who reported adult intimate abuse only. Adjusted rates showed that doubly abused women had significantly greater risk of current harmful alcohol consumption and lifetime drug dependence than women who reported adult abuse only. A significant independent factor for lifetime psychiatric diagnoses was reporting abuse between a woman's parents. Measurement of the population attributable risk found that one-third of the psychiatric diagnoses were attributable to domestic violence.

Adult↗
PubMed1998

How does domestic violence affect women's mental health?

In this paper we compare the mental health of women who reported domestic violence and women who reported no abuse in their lifetime. A longitudinal study was conducted with women, 16 to 74 years (n = 358), who attended the emergency department of a major public hospital in Australia. Our aim was to investigate the nature of symptoms and pattern of mental illness associated with domestic violence. The results of the baseline data reported in this paper showed that women who experienced abuse as adults suffered more ill-effects to their mental health than women who did not experience such abuse; also that women who experienced both adult and child abuse suffered more ill-effects than women who experienced abuse either as an adult or child.

Adolescent↗
PubMed1998

Maternal cigarette smoking and child psychiatric morbidity: a longitudinal study.

OBJECTIVE: Previous studies have linked maternal smoking during pregnancy with behavioral disturbance in children. However, additional evidence is needed to address the causality of the relationship. The present study analyses result from an Australian cohort of 5342 5-year-old children whose mothers were recruited early in pregnancy. METHODS: Smoking history was gathered for prepregnancy, first clinic visit (FCV), late pregnancy, and when the child was 6 months and 5 years of age. Behavior problems at the age of 5 were assessed using a modified Child Behavior Check List (CBCL) shown to have high agreement with the complete CBCL. This resulted in the formation of three scales: internalizing; social, attentional and thought; and externalizing behavior problems, which were then dichotimized at the 90th percentile in each case. Logistic regression was used to model these outcomes as a function of maternal smoking at five time points during which it was assessed. A series of models explored the effect of additional adjustment for confounding. The predictors of attrition (29.5%) throughout the cohort were also identified by multivariate modeling. RESULTS: The final analysis was carried out on a cohort of mother-child pairs for whom data and child behavior outcomes were complete. The mean age of children was 5 years, 6 months with a range from 4 to 6 years. The mean age of mothers at the time of birth of the child was 25 years, with a range from 13 to 47 years. Mothers lost to follow-up were more likely to be younger, single, and less well-educated than those who continued participation, although maternal smoking was not an independent determinant. Unadjusted analyses showed strong associations between externalizing child behavior and maternal smoking during pregnancy and at the 5-year follow-up, with relative risks (RRs) up to 2.6 for children of women smoking at least 20 cigarettes per day at the first antenatal clinic visit. A clear dose-response relationship existed in most relationships with higher levels of smoking being associated with higher rates of externalizing behavior problems. Weaker relationships occurred for internalizing behavior and social, attentional and thought behavior problems. Multivariate analysis of the timing in more detail that the association between maternal smoking and child behavior problems persisted, although the evidence for dose-response diminished. Moreover, it was primarily associated with smoking as determined by questions asked at the FCV (RR = 1.52, 2.03, 2.16) for 1 to 9, 10 to 19, and >/=20 cigarettes per day, respectively, compared with nonsmoking and secondarily by smoking determined at the 5-year follow-up (RR = 1.52, 1.87, 1.29) for 1 to 9, 10 to 19, and >/=20 cigarettes per day respectively, compared with nonsmoking. This association appeared to be independent of a wide range of possible confounders such as maternal age, education, social class, marital status and mental health, gestation at FCV, complications during pregnancy, the child's sex, gestational age at birth, and age at last follow-up. Adjustments were also made for the mother's employment since birth, family structure, and maternal mental health at the time of the CBCL assessment. Associations between externalizing behavior problems and maternal smoking at other times, and those between other behavioral problems examined and maternal smoking were not significant. CONCLUSION: Although previous studies have found evidence for an association between maternal smoking and child behavior problems, the strength of this study lies in its size, its detailed and consistent measurement of maternal smoking, and its ability to control for many social and biological factors linked to maternal smoking and child behavior. (ABSTRACT TRUNCATED)

Adolescent↗
PubMed1998

Genotoxicity studies with the antiestrogen toremifene.

Toremifene, a second-generation triphenylethylene antiestrogen used clinically in the chemotherapy of breast cancer and some other cancers, differs in its nonclinical toxicology from its first-generation congener tamoxifen. Tamoxifen produces DNA adducts and tumors in rat liver, whereas assays for DNA adduct formation with toremifene have been negative to weakly positive, and toremifene does not produce liver tumors in rats. To evaluate further toremifene for possible genotoxicity, it was tested in three standard, in vitro assay--reversion of bacterial point mutations, unscheduled DNA synthesis in cultured hepatocytes from two rat strains, and cytogenetics of human lymphocytes in primary culture--and in one in vivo assay, the mouse, erythrocyte micronucleus assay. The three in vitro assays were conducted with toremifene at up to the limit of cytotoxicity (100 to 250 micrograms/ml, depending on the system). The bacterial mutagenicity and lymphocyte chromosome aberration assays were performed both in the presence and absence of metabolic activation by Araclor-induced, rat liver S-9, while the hepatocyte unscheduled DNA synthesis assay provides intrinsic bioactivation. To test for chromosome damage in vivo, mice were administered up to 2g/kg toremifene once by gavage, and bone marrow was harvested daily, for three days. Normochromatic and polychromatic bone marrow erythrocytes were examined for micronuclei. Toremifene lacked genotoxicity or myelotoxicity detectable by any of the above assays. These findings, together with the reported absence of DNA binding in rat liver, provide evidence that toremifene is not genotoxic.

Animals↗
PubMed1998

Cell proliferation in the livers of male mice and rats exposed to the carcinogen P-dichlorobenzene: evidence for thresholds.

In a previous study, p-dichlorobenzene (pDCB), which is associated with tumorigenicity in male rat kidney and livers of mice of both genders, was found to produce acute increases in cell proliferation in those tissues. To determine whether sustained cell proliferation in the liver in susceptible species correlated with reported carcinogenic effects, we examined the effect of pDCB on cell proliferation in the livers and toxicity to the glutamine synthetase-expressing hepatocyte (GS+) subpopulation of male B6C3F1C3F1 mice and F344 rats. Mice were exposed for up to 4 weeks to 600, the maximally tolerated dose which increased liver tumors, 300 or 150 mg/kg. Rats were exposed to 300, 150 or 75 mg/kg for up to 4 weeks. In mice, the cumulative replicating fraction (CRF) in the livers of the high dose animals was significantly increased 16-fold at 1 week and 4-fold at 4 weeks. The CRF was also increased at 300 mg/kg at 1 week, but this subsided at 4 weeks. No increase was seen in the low dose group. In rats, the CRFs of the livers at 1 week were increased at 300 and 150 mg/kg, but returned to normal at 4 weeks. The size of the hepatic GS+ area was not affected in mice or in rats after 1 week of exposure, but comparable decreases were observed at all exposures at 4 weeks in mice. The data therefore suggest that sustained increases of cell division in the mouse liver may contribute to the increases in liver tumors. The transient increase in rat liver suggests that this is not sufficient to enhance tumor development. The absence of sustained increases of the CRFs at the low dose in mice, which was one-fourth of the hepatocarcinogenic dose, implies the existence of a threshold in pDCB hepatocarcinogenesis.

Animals↗
PubMed1997

An examination of current control strategies for Asian schistosomiasis in the Dongting lake region of China. II. A five year follow-up survey on Qingshan island.

In 1995-1996 we conducted an epidemiological survey in two communities (1656 individuals) on Qingshan island, Hunan province P.R. China, in order to determine the efficacy of current control strategies since their upgrading in 1991. In 1996, the overall prevalence for Schistosoma japonicum, Ascaris lumbricoides, Ancylostoma duodenale, and Trichuris trichiura had decreased moderately since 1991. The age-specific prevalence for S. japonicum for each of the representative age groups decreased slightly, but there was a significant reduction in these prevalences for the 5-9 (P < 0.01), 55-59 (P < 0.05) and the over 60 (P < 0.01) age groups. The 1996 intensities of infection for schistosomiasis were higher for all the age categories except for those aged 0-4 and 25-29 years of age. When the study population was further classified according to the percent uninfected, lightly infected (8-100 eggs/g (epg)), moderately infected (101-400 epg) and heavily infected (> 400 epg) for S. japonicum, there were fewer (5.6%) people infected in 1996 but the proportions of moderately (21.3 vs. 15.5%) and heavily (7.6 vs. 2.3%) infected individuals were higher than those observed in 1991. The reported cases of weakness and hepatomegaly (MSL > or = 3) were significantly lower (P < 0.01) in 1996 for both uninfected and infected (all intensities) individuals. General episodes of diarrhoea were also significantly lower in 1996 for those lightly (P < 0.05) and heavily (P < 0.01) infected. Likewise, the occurrence of splenomegaly (Hackett's > or = 2) was significantly lower among uninfected (P < 0.01) and heavily infected (P < 0.05) patients. In summary, although significant progress has been made in controlling schistosomiasis and other helminth infections in this highly endemic focus for schistosomiasis, there is still room for improvement. Chemotherapy for bovines and humans, mollusciding for Oncomelania control and health education should be initiated and upgraded if the health and well being of these island communities is to further improve.

Adolescent↗
PubMed1997

An evaluation of Schistosoma japonicum infections in three villages in the Dongting lake region of China. I. Prevalence, intensity and morbidity before the implementation of adequate control strategies.

We examined three Chinese villages (one farming village and two fishing villages) in an area highly endemic for schistosomiasis japonica in order to study the prevalence, intensity of infection and the associated morbidities before the implementation of adequate control strategies. Socio-economic status, medical histories including the frequency and type of water contact, physical examinations, parasitological examinations and questionnaires relevant to the knowledge of schistosomiasis were performed on a random sample of 1542 individuals (45% female; 55% male). The prevalence of Schistosoma japonicum was 9.4% in the farming village and 16.5 and 26.2% in the fishing villages. Eighty-three percent of the infected population had light infections (8-100 eggs per gram stool (epg)) and only 6% had heavy infections (> 400 epg). Both the prevalence and intensity of infection varied significantly (P < 0.01) with the frequency of water contact. All the morbidity indicators (weakness, inability to work, diarrhoea, hepatomegaly and splenomegaly) were significantly higher (P < 0.01) among those infected with S. japonicum. Knowledge of schistosomiasis, in general, was unsatisfactory in all three villages; 12.4% of the population was infected when their knowledge of schistosomiasis was good, whereas 26.6% of the population was infected when their knowledge was poor. Further, it appears that schistosomiasis control based on selective chemotherapy (praziquantel) of randomly selected stool-positive individuals was ineffective in significantly reducing the prevalence of S. japonicum and its associated clinical manifestations in the villages under study.

Adolescent↗
PubMed1997

Chemicals with carcinogenic activity in the rodent liver; mechanistic evaluation of human risk.

A wide variety of chemicals, both naturally occurring and synthetic, have exhibited carcinogenic activity in rodent liver. Some are clearly DNA reactive whereas others produce only epigenetic effects. Hepatocarcinogens are categorized according to these properties and the characteristics of examples of both types are reviewed. DNA-reactive rodent hepatocarcinogens represent human cancer risk even at non-toxic exposures, whereas epigenetic agents pose either no risk because their effects are specific to rodents, or a risk only at high exposures at which they produce the same cellular effects in humans that are the basis for their carcinogenic activity in rodents.

Animals↗
PubMed1997

End-of-life decision-making: community and medical practitioners' perspectives.

OBJECTIVE: To examine current attitudes and knowledge of the community and medical practitioners in Queensland to end-of-life decisions. DESIGN: Cross-sectional survey by postal questionnaire. PARTICIPANTS: 387 general practitioners and medical specialists and 910 community members from the Queensland electoral roll. MAIN OUTCOME MEASURES: Responses to five questions about end-of-life decision-making, and to legislative changes relating to such decisions. RESULTS: The overall response rate for medical practitioners was 67% and for community members was 53%. 78% of community members (age adjusted) and 54% of doctors thought that a doctor should comply with a patient's request to turn off a life-support system; 68% of doctors through people would still ask to have their life ended even if pain were controlled, compared with 54% of community members; 70% of community members thought the law should be changed to allow active voluntary euthanasia, compared with 33% of doctors; and 65% of community members thought that a doctor should be allowed by law to assist a terminally ill person to die, but only 36% of doctors agreed. 79% of doctors and 75% of community members agreed that people would still ask for assistance to end their lives even if optimal palliative care were freely available. CONCLUSION: Community members supported greater choice and control over end-of-life decisions, while doctors were less supportive of some of the options canvassed. In a climate of community participation in health care decisions, it is important to better understand the basis and meaning of these different views. Further detailed research is recommended.

Adolescent↗
PubMed1997

A fluoroquinolone antibiotic with a methoxy group at the 8 position yields reduced generation of 8-oxo-7,8-dihydro-2'-deoxyguanosine after ultraviolet-A irradiation.

We have previously reported that two fluoroquinolone antibiotics gave rise to 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) in DNA of cells concurrently exposed to UV-A and that this correlated with clinical phototoxicity. To determine the structural basis for generation of oxidative damage, the ability of two synthetic fluoroquinolone candidate antibiotics, Bayer 12-8039 (12-8039) and Bayer Y3118 (Y3118), to give rise to 8-oxo-dG in cultured liver epithelial cells was compared. 12-8039 contains a methoxy group at the 8 position of the quinolone nucleus, whereas Y3118 contains a chlorine group at the same position. Y3118 produced dose-dependent increases in 8-oxo-dG formation in cultured cells after UVA irradiation, whereas the 8-OCH3-substituted 12-8039 produced no increase. Also, after exposure to 20 J/cm2 UVA, UV spectral scans of both compounds revealed that Y3118 underwent photodegradation whereas 12-8039 was stable. These results demonstrate that the presence of an 8-OCH3 group on the quinolone nucleus is important for the reduction of photogeneration of oxidative DNA damage and photodegradation in the presence of UVA irradiation. From this, we suggest that 12-8039 has little phototoxic potential.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Clinical markers in CSF for determining neurologic deficits after thoracoabdominal aortic aneurysm repairs.

BACKGROUND: Spinal cord ischemia is a major cause of morbidity and mortality after thoracoabdominal aortic aneurysm operations. The incidence of paraplegia is high even in experienced institutions. METHODS: We investigated whether neurotransmitter excitotoxicity is associated with neurologic deficits after thoracoabdominal aortic aneurysm operations. We hypothesized that patients with spinal cord injury would manifest elevated levels of excitatory amino acids in their cerebrospinal fluid. Sixteen patients undergoing thoracoabdominal aortic aneurysm operations had cerebrospinal fluid drawn through lumbar spinal drains preoperatively, intraoperatively, and postoperatively. Excitatory amino acid levels (glutamate, aspartate, glycine) were measured using high-performance liquid chromatography. Excitatory amino acid levels were compared in patients who exhibited no neurologic deficits postoperatively (group I; n = 12) with patients who had clinically evident lower extremity and cerebral neurologic deficits (group II; n = 4). RESULTS: Significant elevations in glutamate and aspartate levels from baseline (p < 0.05) were limited to group II. Excitatory amino acid levels in group II were significantly elevated (p < 0.05) compared with those observed in group I. Glutamate levels were especially increased during aortic cross-clamping and late reperfusion, whereas aspartate levels were increased only during late reperfusion. CONCLUSIONS: These data suggest that neurotransmitter excitotoxicity plays a significant role in central nervous system injury.

Aged↗
PubMed1997

Abdominal aortic tailoring for renal, visceral, and lower extremity malperfusion resulting from acute aortic dissection.

PURPOSE: The treatment of ischemic complications that result from aortic dissection is a challenging and controversial problem. The purpose of this study was to evaluate aortic tailoring in the management of acute aortic dissection associated with visceral, renal, or lower extremity ischemia. METHODS: We retrospectively reviewed the clinical courses of seven consecutive patients (five men, two women) with a median age of 68 years (range, 48 to 74 years) from January 1994 to January 1997. All patients underwent an abdominal aortic tailoring procedure for relief of ischemic complications associated with acute aortic dissection (type IIIB, n = 6; type I, n = 1) and a normal-sized aorta. RESULTS: All seven patients survived and recovered full mesenteric, renal, and lower extremity function. Two patients required temporary hemodialysis in the immediate postoperative period. There has been no significant dilatation of the tailored aortic segments, with an average follow-up of 19 months (range, 1 to 30 months). CONCLUSIONS: Abdominal aortic tailoring represents a safe and effective method for treating ischemic complications associated with acute aortic dissection and a normal aortic luminal diameter.

Acute Disease↗
PubMed1997

Impact of a critical pathway on the results of carotid endarterectomy in a tertiary care university hospital: effect of methods on outcome.

PURPOSE: A carotid endarterectomy critical pathway (CP) targeting a 3-day postoperative course was introduced in March 1994. This retrospective analysis assesses its impact on operative results, postoperative length of stay (POD), and cost of hospitalization (COH). METHODS: One hundred eighty-six patients who underwent 201 carotid endarterectomy procedures from Nov. 1992 to Feb. 1994 (Pre-CP; n = 67) and from Apr. 1994 to Jul. 1995 (Post-CP; n = 134) at Johns Hopkins Hospital, a tertiary care referral center, were evaluated. RESULTS: The Pre-CP and Post-CP groups had similar risk factors, postoperative morbidity rates, and mortality rates. Furthermore, they had similar mean POD (Pre-CP, 6.0 +/- 0.5 days; Post-CP, 5.7 +/- 0.6 days; p = 0.79) and COH. However, only 85 of the Post-CP (63%) patients were actually placed on the CP (CP-starters); the mean POD was 3.4 +/- 0.3 days among these CP-starters (p < 0.0001) and 2.8 +/- 0.1 days among the 74 Post-CP patients (55%) that remained on the pathway (CP-finishers; p < 0.0001). The mean COH was reduced from $12,881 (Pre-CP) to $9701 for the CP-starters (p = 0.01) and to $8572 for the CP-finishers (p = 0.0001). However, we found that only 47 of the Pre-CP patients (70%) would have been eligible for the CP, and the mean POD among those cases was 4.2 +/- 0.4 days, which was not different than the mean POD among the CP-starters (p = 0.17). The mean COH of the eligible Pre-CP cases, $9508, was not significantly different from the COH of the CP-starters (p = 0.97). CONCLUSIONS: This subset analysis emphasizes the importance of establishing an accurate "control" group when studying a CP, because using all of the Pre-CP cases as the "control" group in the original analysis, including patients who would not have been candidates for the CP, clearly overstated the beneficial impact of the CP.

Analysis of Variance↗
PubMed1997

Assessment of chronic toxicity and carcinogenicity in rats of Wingstay 100, a rubber antioxidant/antiozonant.

The chronic toxicity and carcinogenicity of Wingstay 100 (W 100), a rubber antioxidant/antiozonant, were studied in Fischer 344 (F 344) rats in two chronic studies. Earlier genetic studies indicated that the product had weak activity in a bacterial mutation assay, but lacked activity in chromosomal aberration assays. In an one year study, both genders of F 344 rats were exposed to 53, 310 or 1900 ppm in NIH-07 diet for 52 weeks, and sacrifices were made at 38, 52 and 64 weeks. No test substance related deaths occurred, although the high dose of 1900 ppm caused a decrease in body weight gain and food consumption in both genders. Red blood cell mean corpuscular volume was significantly increased at 38 weeks, accompanied by a significant decrease in mean corpuscular hemoglobin concentration. At 52 weeks, the red blood cell count and hemoglobin values were also significantly decreased in high dose animals of both genders. Total bilirubin and cholesterol were increased in high dose animals of 38 and 52-week sacrifices. During the 3 month recovery, hematology parameters, bilirubin and cholesterol returned to control values. Total protein was reduced in high dose animals of both genders, throughout the entire exposure and recovery periods. W 100 also produced increases in relative liver, spleen, heart and kidney weights in high dose animals. Both genders of all W 100 groups exhibited significant increases in urothelial cell proliferation (measured by PCNA) and adaptive hyperplasia. No regenerative hyperplasia, preneoplasia, or neoplasia were present. There was microscopic evidence of extramedullary erythropoiesis in the spleen and liver of high dose animals in both genders, otherwise no other pertinent microscopic finding was evident. In parallel, an accelerated bioassay (ABA) was conducted, which is a mechanistic initiation/promotion carcinogenicity study designed to assess tumor induction and promotion potential of a test substance in major organs of carcinogenesis. The present study was conducted in male F 344 rats for 38 weeks. The target sites chosen for the ABA were liver and urinary bladder and the dose for W 100 was 1900 ppm previously established to be a toxic dose. The liver tumor initiator was diethylnitrosamine (DEN), and the urinary bladder initiator was N-butyl N-(4-hydroxybutyl) nitrosamine (BBN). The initiators were administered during the first 14 weeks followed by the promoters. The promoters, phenobarbital (PB) for the liver and nitrilotriacetate (NTA) for the urinary bladder, were administered during the last 24 weeks of the study after the test substance. The study had 11 test groups including a negative control. The critical comparisons for initiating activity were conducted between groups 3 (PB) and 6 (W 100 + PB) for the liver and groups 8 (NTA) and 11 (W 100 + NTA) for the urinary bladder. The critical comparisons for promoting activity were conducted between groups 2 (DEN) and 5 (DEN + W 100) for the liver and groups 7 (BBN) and 10 (BBN + W 100) for the urinary bladder. There were 26 and 38-week sacrifices. In this study, most body weight reductions were due to DEN. At 26 weeks, significant increases in liver weights were present in all PB-exposed groups. Significant increases in renal weights occurred in all NTA, BBN and DEN groups. A similar organ weight pattern was present at 38 weeks. At 26 weeks, there were hepatocellular (33%) and urothelial (67%) tumors present in positive control groups (DEN/DEN + PB/BBN/BBN + NTA). In contrast, in the DEN + W 100 (5) and the BBN + W 100 (10) groups no tumors were present indicating absence of promotion. In addition, no tumors were present in groups 6 (W 100 + PB) or 11 (W 100 + NTA) indicating absence of initiation. At 38 weeks, the incidences of hepatocellular adenomas and carcinomas in positive control group (DEN) was 44%. The incidence of urothelial adenomas and carcinomas was 67% in group 7 (BBN). In contrast, groups 5 (DEN + W 100) or group 10 (BBN + W 100) had

Animals↗
PubMed1997

Mechanistic studies on genotoxicity and carcinogenicity of salicylazosulfapyridine an anti-inflammatory medicine.

Salicylazosulfapyridine (SASP), which has been in clinical use for over 50 years, was reported by the National Toxicology Program to increase rat (F344 strain) urinary bladder and mouse (B6C3F1 hybrid) liver tumours under ad libitum (AL) feeding conditions, while under a feed restriction (FR) regimen, these tumours were not increased. The present investigations were undertaken to assess the implications of these results for the safety of SASP in humans. SASP and its 2 major metabolites, 5-aminosalicylic acid (ASA) and sulfapyridine (SP) were tested for in vivo induction of micronuclei in mouse bone marrow cells with or without prefolic treatment and for in vivo formation of DNA adducts in rat and mouse liver and urinary bladder. None exhibited mutagenicity or DNA reactivity. SASP and SP have induced sister chromatid exchanges and micronuclei (MN) in cultured human lymphocytes in the absence of liver activation enzymes and in B6C3F1 mice (but not in rats) MN in bone marrow and peripheral RBC. Treatment with folate reduces the frequency of MN. Perhaps the short (28 days) RBC lifespan in mouse underlies the sensitivity of this species. Thus, SASP without folate supplementation is an aneuploidogen. In a 2-year study in AL fed SASP-treated (high dose 337.5 mg/kg) rats, urinary pH was increased and urinary specific gravity was reduced at 60 weeks. At the end, this SASP group showed urothelial hyperplasia and papillomas in the urinary bladders of male rats primarily. In the FR high dose SASP group, the hyperplasia was reduced from 82% to 14%. At the end of 2 years, the incidence of multi-organ leukemia was reduced in both AL and FR high dose SASP groups. Thus, SASP caused intraluminal bladder changes in the rat (especially males) consisting of chronic urothelial stimulation, concretions, hyperplasia which resulted in neoplasia. In the mouse, because of species differences in liver ratios (mouse > rat) and, increasing (3 times higher) liver perfusion in the mouse, compared to the rat, there was hepatocellular toxicity and resulting preneoplasia and neoplasia within 2 years. These findings occurred in all AL SASP groups (flat curve without dose response); but were reduced under FR conditions. In this species, the multiorgan lymphoma incidence was reduced in both AL and FR high dose SASP groups. Thus, SASP and its major metabolites are not genotoxic. Folate deficiency associated with SASP administration is probably responsible for aneuploidy in lymphocytes and erythrocytes. SASP does not induce neoplasia directly in either livers, urinary bladders or other organs. Accordingly, SASP is judged to pose no carcinogenic risk to humans.

Aminosalicylic Acids↗