UMLS:C0019158 - FACTA Search

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Query: UMLS:C0019158 (hepatitis)
30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the study was to investigate the frequency of nutritional anemia among western venezuelan indians. Three hundred and ninety nine Yucpa indians from the communities of Aroy, Marewa and Peraya were studied. The concentrations of hemoglobin, serum iron, total iron binding capacity, serum ferritin, serum folate and serum vitamin B12 and the frequency of anemia and nutrient deficiency were determined. Anemia was found in 71.7% of people from Aroy, 52.25 from Marewa and in 74.4% from Peraya. No nutrient deficiencies were found in 48.1% of cases with anemia, while iron deficiency anemia was present in 39% of the population studied, and folate and or vitamin B12 deficiency were associated with anemia in only 12.9% of cases. The high frequency of anemia, unrelated to nutrient deficiency, among the Yucpa indians, is attributed to the prevalence of chronic infectious diseases such as hepatitis and parasitic infections, as well as skin and respiratory infectious processes.
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PMID:[Anemia in indigenous population of the West of Venezuela]. 1053 52

The risk of a work related HIV-exposure or infection to midwives, or other HCW, in attending waterbirths of (possible unrecognized) HIV-positive women is unknown. Our goal was the quantification of the loss of blood of the childbearing woman after a waterbirth into the waterpool, in taking pool-water-samples of 14 different waterbirths and measuring the hemoglobin in the plasma, and then correlating the mean found loss of blood and the mean quantity of poolwater with a hypothetical HIV-RNA viral load of 10(3)-10(6) copies per milliliters (ml) blood. All attended waterbirths were evaluated with a questionnaire regarding: parity of the child-bearing woman; serostatus for HIV/Hepatitis-B (HBV) and Hepatitis-C (HCV); length of the birth-process; perineum-rupture or not, etc. Questions concerning the HCW in implementing universal precautions like: type of gloves and garment used, if at all; duration of water contact with the hands; existing skin lesions; HBV-vaccination-status; years of professional experiences as a midwife; how many waterbirths attended etc. were also evaluated. The mean calculated loss of blood into the pool was 300 ml, the mean pool-water content 633 liters. With a hypothetical (maximal) HIV-RNA viral load of 10(6) copies per ml blood, we calculated a mean HIV-RNA viral load of 476 copies per ml pool-water. We also found 37% of the interviewed midwives (n = 14) to have skin lesions on hands or fingers; 1 received splashes into her (unprotected) face and 1 was not immunized against HBV. The mean loss of blood of 300 ml into the pool is a relevant amount. The skin-contact of the HCW with the potentially contaminated water is the norm, because of the failure of the type of used gloves. Because of the diluting effect of the poolwater, we estimate the potential risk for a HIV-exposure to intact skin as minimal and, therefore a potential HIV-infection as "low level" and to be unlikely. However, a risk for nosocomial HBV-infection is significantly higher. We recommend wearing long-sleeved gloves, waterproofed garment, and HBV-vaccination to all HCW.
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PMID:[Water births and the exposure to HIV]. 1096 81

Thirty-two patients were enrolled in an open-label, dose/schedule ranging clinical trial to evaluate the efficacy and tolerability ofliposomal amphotericin B (Ambisome) in the treatment of visceral leishmaniasis. All patients received a dose of 2mg/kg daily for the first 4 days, followed by a single repeat dose of 2mg/kg at day 10 in 4 patients (total dose 10mg/kg); repeat doses on days 5, 6, and 10 in 13 patients (total dose 14mg/kg); or daily doses were continued on days 5 through 10 in 15 patients (total dose 20mg/kg). Patients had a mean age of 9 years, ranging between 3 and 26 years. Their mean weight was 25.9kg, ranging between 9.5kg and 75kg. All patients had splenomegaly, 31/32 had hepatomegaly, and 20 patients tested had leishmania documented on splenic aspirate. Six of the 32 patients were treated after relapse following antimony therapy. The duration of illness prior to therapy was a mean of 2 months, ranging between 2 weeks and 23 months. During and after treatment, there were significant reductions in liver and spleen sizes, and significant increases in body weight, hemoglobin levels and white blood cell counts. All patients showed initial cure at the 1 month follow-up. Seven patients relapsed between 2 and 6 months after the start of treatment. There was no dose relationship to the occurrence of relapse. The relapse rate in children 5 years of age or less was 7/15 (47%). Associated causes of relapse were refractory disease (i.e., previous relapses) in 2, severe malnutrition in 1, and concurrent disease (meningococcal meningitis) in 1. In the other 2 cases, no associated event was observed except young age (ages 3 and 5 years). One relapsed patient was treated successfully with 14 days of lipid amphotericin B, and the others were cured by use of antimony for 20 to 30 days. There were no dose related adverse events. The most common event was fever which occurred in 13/32 patients (41%); 3/4 patients in the 10mg dose group, 7/13 in the 14mg dose group, and 3/15 in the 20mg dose group. Three patients had cardiac arrhythmia, one also with myocarditis diagnosed 2 weeks after therapy was discontinued. One patient developed hepatitis after dose 3 and the drug was discontinued. We concluded that liposomal amphotericin B is effective in a daily dose of 2mg/kg given for 5-10 doses as an initial cure, but that relapse occurs in young children, particularly those with documented treatment resistant disease or concurrent malnutrition or infection. Patients should be carefully monitored for these risk factors before and during the months alter therapy, and for the occurrence of arrhythmia, cardio-pulmonary effects or hepatotoxicity. This treatment provides an important advance over previously used antimony therapy and appears to be more effective and well-tolerated than non-lipid amphotericin B.
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PMID:Efficacy and Tolerability of Liposomal Amphotericin B (Ambisome) in the Treatment of Visceral Leishmaniasis in Brazil. 1110 43

Viral infection has been shown to induce aplastic anemia, unidentified types of hepatitis being the most common cause for aplastic anemia-associated viral hepatitis. The survival rate for this group of patients after bone marrow transplantation with stem cells from an HLA-matched sibling is not well known. The aim of this study was to determine the prevalence of hepatitis G virus (HGV) and transfusion transmitted virus (TTV) infection in non-A, non-B, non-C hepatitis associated-aplastic anemia (HAAA) patients, and to define the role of bone marrow transplantation (BMT) as a therapeutic modality for this disease. Sixty-eight patients (43 males and 25 females) with aplastic anemia, underwent allogeneic BMT at the Hadassah University Hospital between 1981 and 1997. Onset of hepatitis was defined as jaundice and elevated alanine aminotransaminase (ALT) levels. Onset of aplastic anemia was defined as the first date on which varying degrees of pancytopenia occurred: hemoglobin level below 10 g/dl, WBC below 2 x 10(9)/l and low platelet count 10 x 10(10)/l. Serial serum samples from HAAA patients were assayed for virological and/or serological markers of hepatitis A, B, C, D, E, G viruses, TTV and parvovirus B19. Seventeen of the 68 patients with aplastic anemia (25%) suffered from hepatitis, 12 males and five females, ages 5 to 36 years. The mean interval between onset of hepatitis and first indication of aplastic anemia was 62 days (range 14-225 days). The development of aplastic anemia was unrelated to age, sex or severity of hepatitis. Ten of the 17 patients (59%) achieved complete ALT recovery prior to the diagnosis of aplastic anemia. Serum samples were available for 15 patients; none had evidence of acute or active hepatitis A, B, C, D, E, G and TTV virus infection at the time of diagnosis. Parvovirus B19 DNA sequences were not detectable in 10 of 12 tested cases; two positive results were detected in serum samples obtained after blood transfusion, making the analysis of these positive results difficult. All 17 patients underwent BMT. The mean post-BMT follow-up period was 38 months (range 1 day-123 months), five patients (30%) died 1 to 160 days post BMT, and 12 (70%) are alive 31 to 123 months after BMT. Relapsing hepatitis was not observed in any of the patients. In conclusion, HAAA is a disease of the young and the etiologic agent associated with HAAA remains unknown. HGV, TTV and parvovirus B19 sequences were not detected in any of the HAAA cases. The survival rate after BMT with stem cells from an HLA-matched sibling is similar to that for patients with non-hepatitis-associated aplastic anemia.
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PMID:Lack of known hepatitis virus in hepatitis-associated aplastic anemia and outcome after bone marrow transplantation. 1128 88

In the liver of adult mice bearing an Ehrlich carcinoma on the leg, progressively hypoxic and displaying reactive hepatitis but not metastatic dissemination, extramedullary hemopoiesis was detected. Electron microscopy revealed mainly erythropoietic islands and scattered megakaryocytes in maturation stages up to the platelet-releasing phase. Erythropoietic cells expressed an embryonic-type of hemoglobin, which is more adequate to oxygenate hypoxic environments than the adult type. They were positive for the peroxidase reaction due to the presence of hemoglobin and could furthermore be visualized by the blue-excited red autofluorescence of protoporphyrin IX. Extramedullary hemopoiesis, one of the various examples of reactivation of fetal features in the liver associated with carcinogenesis, is supposed to be compensatory for the loss of blood cells induced by the tumor. Reviewing this process has the purpose of raising the question whether the fetal features are better adapted than adult ones to the metabolic and physiological characteristics of a tumor-influenced organism.
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PMID:Hemopoiesis in the liver of adult tumor-bearing mice. 1172 68

Recurrence of hepatitis C virus (HCV) infection after orthotopic liver transplantation is a major cause of graft failure. The aim of our study was to determine the safety, efficacy, and tolerability of combination therapy with interferon and ribavirin in the treatment of recurrent hepatitis after liver transplantation. Twenty-six patients (18 men) with histologically established HCV recurrence after liver transplantation for cirrhosis secondary to chronic HCV infection were treated with a combination of interferon alfa-2b (3 million units three times weekly) and ribavirin (800 to 1,000 mg/d). Dosage modifications were according to a standard protocol incorporating laboratory values and clinical side effects. Fifty percent of patients completed 1 year or more of therapy. On an intention-to-treat basis, nine patients (35%) showed an end-of-treatment virological response. Six of these nine patients completed greater than 6 additional months of follow-up, and all have had sustained virological responses. A histological response (decrease in histological activity index > or = 2) was seen in 75% of virological responders and 67% of nonresponders. Adverse events requiring dose modification or cessation of therapy occurred in 66% of patients. Adjuvant therapies used to support hemoglobin levels included erythropoietin and red blood cell transfusions. There were no independent pretreatment predictors of a virological response, perhaps because of the small sample size. Combination therapy with interferon and ribavirin may be beneficial in patients with recurrent HCV after liver transplantation. The majority of patients require dose modifications because of side effects. Histological response is common in virological nonresponders.
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PMID:Treatment of posttransplantation recurrence of hepatitis C with interferon and ribavirin: lessons on tolerability and efficacy. 1208 17

Theophylline is an alkaloid found in tea (Thea sinensis) and chocolate and is structurally related to caffeine and theobromine. Theophylline is used as a pharmaceutical agent. It stimulates the heart and central nervous system, relaxes the smooth muscles of the bronchi and blood vessels, and causes diuresis. The drug is used mainly as a bronchodilator in obstructive airway diseases, such as bronchial asthma, and for myocardial stimulation. Theophylline was nominated for toxicologic and carcinogenicity testing as a representative of the purine structural subclass, particularly because of its relationship to purines such as caffeine, 1-methyl-3-hydroxyguanine, and 3-hydroxy-1-methylxanthine, the latter two compounds having been shown to induce sarcomas in rats. Additional reasons for testing theophylline included its widespread use in humans as a pharmaceutical agent, its possible genotoxicity in vitro, and the lack of information on its potential toxicity and/or carcinogenicity under conditions of chronic oral usage. Based on reported teratogenicity and testicular toxicity, it was also recommended that reproductive studies be included in the evaluation of theophylline. The oral route of administration was selected because it is the primary route of human exposure, and the gavage route was selected because it mimics the pharmaceutical use of theophylline in humans. Male and female F344/N rats and B6C3F1 mice were given theophylline (greater than 99% pure) in feed or in corn oil by gavage for 16 days or 14 weeks or in corn oil by gavage for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow, and mouse peripheral blood. 16-DAY FEED STUDY IN RATS: Groups of five male and five female F344/N rats were given 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm theophylline in feed for 16 days, which resulted in approximate daily doses of 50, 100, 250, 450, or 1,000 mg theophylline/kg body weight to males and 75, 150, 250, 450, or 1,100 mg/kg to females. All rats survived until the end of the study. The final mean body weights and body weight gains of 8,000 ppm males and females were significantly less than those of the controls. The absolute and relative testis weights of 4,000 ppm males were significantly greater than those of the controls. Increased incidences of uterine hypoplasia were observed microscopically in exposed groups of females. 16-DAY GAVAGE STUDY IN RATS: Groups of five male and five female F344/N rats were given 0, 12.5 (twice daily), 25 (once daily), 50 (once daily), 50 (twice daily), 100 (once daily), 200 (once daily), 200 (twice daily), or 400 (once daily) mg theophylline/kg body weight in corn oil by gavage. All rats receiving 400 mg/kg once daily and all but one female receiving 200 mg/kg twice daily died during the study. In groups dosed once daily, final mean body weights and body weight gains of males receiving 100 or 200 mg/kg and mean body weight gains of females receiving 50, 100, or 200 mg/kg were less than those of controls. The final mean body weights and body weight gains of groups receiving theophylline twice daily were generally similar to those of groups receiving the same daily dosages once daily. Clinical findings included rapid or labored respiration, hunched posture, and squinting. In groups dosed once daily, absolute and relative uterus weights of females receiving 100 or 200 mg/kg once daily were significantly less than those of the controls, and the absolute and relative uterus weights of females receiving 100 mg/kg once daily were significantly less than those of females receiving 50 mg/kg twice daily. Uterine atrophy was observed in three females receiving 200 mg/kg twice daily. Periarteritis of the mesenteric arteries was observed in two males and two females receiving 400 mg/kg once daily. 16-DAY FEED STUDY IN MICE: Groups of five male and five female B6C3F1 mice were given 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm theophylline in feed for 16 days, resulting in approximate daily doses of 250, 475, 950, 1,800, or800, or 2,000 mg theophylline/kg body weight to males and 300, 450, 1,225, 2,000, or 4,375 mg/kg to females. All mice survived until the end of the study. Final mean body weights of 4,000 and 8,000 ppm females and mean body weight gains of 2,000, 4,000, and 8,000 ppm females were significantly greater than those of the controls. Feed consumption by exposed groups was similar to that by the controls, except that by the 8,000 ppm males, which was approximately 40&percnt; the amount of feed consumed by the control group. Histopathologic examinations were not performed due to the absence of mortality and significant exposure-related lesions. 16-DAY GAVAGE STUDY IN MICE: Groups of five male and five female B6C3F1 mice were given 0, 12.5 (twice daily), 25 (once daily), 50 (once daily), 50 (twice daily), 100 (once daily), 200 (once daily), 200 (twice daily), or 400 (once daily) mg theophylline/kg body weight in corn oil by gavage. Three males and all females receiving 400 mg/kg once daily died on day 1. There were no significant differences in final mean body weights or body weight gains. There were no histopathologic findings attributed directly to theophylline. 14-WEEK FEED STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 1,000, 2,000, or 4,000 ppm theophylline in feed for 14 weeks, which resulted in approximate daily doses of 75, 125, or 250 mg theophylline/kg body weight to males and 75, 125, or 275 mg/kg to females. The final mean body weight of 1,000 ppm females was significantly greater than that of the control group. Feed consumption by exposed groups was similar to that by the controls. Mean cell volume and mean cell hemoglobin were significantly greater in males exposed to 2,000 or 4,000 ppm than those in the control group. Segmented neutrophil counts of all groups of exposed females were significantly greater than that of the control group. The absolute and relative kidney weights of 4,000 ppm males were significantly greater than those of the controls, and there was an exposure-related increase in the severity of nephropathy in males. Exposure-related increases in the incidences of mesenteric and/or pancreatic periarteritis were observed in males and females. 14-WEEK GAVAGE STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 37.5, 75, or 150 mg theophylline/kg body weight in corn oil by gavage for 14 weeks. One male and one female receiving 150 mg/kg died before the end of the study. The mean body weight gain of 150 mg/kg females was significantly greater than that of the controls. Mean cell volume of 150 mg/kg males and mean cell hemoglobin of all groups of dosed males were significantly greater than those of the control group. There were slight dose-dependent increases in the incidences of mesenteric periarteritis in dosed males and females. 14-WEEK FEED STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were given 0, 1,000, 2,000, or 4,000 ppm theophylline in feed for 14 weeks, resulting in approximate daily doses of 175, 400, or 800 mg theophylline/kg body weight to males and 225, 425, or 850 mg/kg to females. All mice survived until the end of the study. The final mean body weights and body weight gains of all exposed groups of males and females were significantly less than those of the controls. Feed consumption by exposed groups was similar to that by the controls. Leukocyte, segmented neutrophil, and lymphocyte counts of 4,000 ppm males were significantly greater than those of the controls. Leukocyte and segmented neutrophil counts of 2,000 or 4,000 ppm females were significantly greater than those of the controls. There were no histopathologic findings attributed directly to theophylline exposure. 14-WEEK GAVAGE STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were given 0, 75, 150, or 300 mg theophylline/kg body weight in corn oil by gavage for 14 weeks. Three males and all females receiving 300 mg/kg, one 75 mg/kg male, and one control female died before the end of the study. Final mean body weights and body weight gains of 150 and 300 mg/kg males were significantly less than those of the controls. Mean cell volume and mean cell hemoglobin of 300 mg/kg males were significantly greater than those of the controls. There were no histopathologic findings attributed directly to theophylline treatment. 2-YEAR GAVAGE STUDY IN RATS: Groups of 50 male and 50 female rats were given 7.5, 25, or 75 mg theophylline/kg body weight in corn oil by gavage for 2 years. Survival and Body Weights: There were no significant differences in survival between dosed and control groups. Final mean body weights of all groups of dosed males and females were significantly less than those of the controls. Pathology Findings: There were no significantly increased incidences of neoplasms in dosed rats. The incidence of chronic inflammation of the mesenteric arteries was significantly increased in males receiving 75 mg/kg compared to the controls. There were doserelated negative trends in the incidences of mammary gland fibroadenoma and fibroadenoma or carcinoma (combined) in females; these differences correlated with decreased body weights. 2-YEAR GAVAGE STUDY IN MICE: Groups of 50 male B6C3F1 mice were given 0, 15, 50, or 150 mg theophylline/kg body weight and groups of 50 female B6C3F1 mice were given 0, 7.5, 25, or 75 mg/kg in corn oil by gavage for 2 years. Survival and Body Weights: Survival of 150 mg/kg males was significantly less than that of the controls. The final mean body weights of 150 mg/kg males, 25 mg/kg females, and 75 mg/kg females were significantly less than those of the control groups. Pathology Findings: There were no treatment-related increases in incidences of nonneoplastic lesions or neoplasms. In males and females, there were decreased incidences of hepatocellular adenoma and of the combined incidences of hepatocellular adenoma or carcinoma compared to the controls. Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms in the liver consistent with Helicobacter hepaticus infection. The incidences of these liver lesions in 150 mg/kg males were significantly lower than those in control males. Increases in the incidences of hepatocellular neoplasms in male mice have been shown to be associated with H. hepaticus infection when hepatitis is also present. Because of this association, interpretation of the decreased incidence of liver neoplasms in male mice was more difficult. Incidences of lesions at other sites in this study were not considered to have been significantly impacted by H. hepaticus infection or its associated hepatitis. GENETIC TOXICOLOGY: Theophylline was not mutagenic in Salmonella typhimurium, with or without metabolic activation (S9). It induced sister chromatid exchanges but not chromosomal aberrations in cultured Chinese hamster ovary cells. The positive sister chromatid exchange response was noted only in the absence of S9. In vivo, a mouse bone marrow sister chromatid exchange test showed positive results at a standard 23-hour harvest time; however, this test was not repeated and the response is unconfirmed. An in vivo mouse bone marrow chromosomal aberrations test, that employed both standard and extended exposure protocols, gave negative results. The frequency of micronucleated erythrocytes was determined in peripheral blood of male and female mice exposed to theophylline in dosed feed or in corn oil by gavage for 14 weeks. No significant increases in the frequencies of micronucleated cells were seen in male or female mice in either of the studies. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of theophylline in male or female F344/N rats administered 7.5, 25, or 75 mg/kg. There was no evidence of carcinogenic activity of theophylline in male B6C3F1 mice administered 15, 50, or 150 mg/kg or female B6C3F1 mice administered 7.5, 25, or 75 mg/kg. Gavage administration of theophylline caused chronic inflammation of the mesenteric arteries in dosed male rats. Decreased incidences of mammary neoplasms in female rats were likely associated with lower body weights. There were dose-related decreases in the incidences of hepatocellular adenoma and hepatocellular carcinoma in male and female mice. Synonyms: 3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione; 1,3-dimethylxanthine; 1H-purine-2,6-dione; NSC 2066; pseusdotheophylline; theocin; theophyllin; theophylline, anhydrous Trade names: Accurbron; Aerobin; Aerolate III; Afonilum; Aminophylline; Aquaphyllin; Armophylline; Asmalix; Bilordyl; Bronchoretard; Bronkodyl; Cetraphylline; Constant-T; Diffumal; Duraphyl; Duraphyllin; Elixicon; Elixophyllin; Euphylline L.A.; Euphylong; LaBID; Labophylline; Lanophyllin; Lasma; Liquophylline; Optiphyllin; Parkophyllin; Phylocontin; Physpan; Pro-Vent; PulmiDur; Pulmo-Timelets; Quibron; Respbid; Rona-Phyllin; Sabidal; Slo-bid; Slo-Phyllin; Solosin; Sustaire; Tefamin; Teobid; Teofyllamin; Tesona; Theal tablets; Theo-24; Theobid; Theocap; Theochron; Theoclear; Theocontin; Theo-Dur; Theofol; Theograd; Theolair; Theolan; Theolix; Theophyl; Theoplus; Theo-Sav; Theosol; Theospan; Theostat; Theovent; TheoX; T-Phyl; Truphylline; Uni-Dur; Unifyl; Uniphyl; Uniphyllin; Xanthium
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PMID:NTP Toxicology and Carcinogenesis Studies of Theophylline (CAS No. 58-55-9) in F344/N Rats and B6C3F1 Mice (Feed and Gavage Studies). 1257 77

3'-Azido-3'-deoxythymidine (AZT) is the most widely used and evaluated chemotherapeutic agent for the treatment of persons with acquired immune deficiency syndrome (AIDS) and persons seropositive for human immunodeficiency virus (HIV). The National Cancer Institute nominated AZT for toxicity and carcinogenicity studies because of the impending large-scale use of AZT in the treatment of adult patients with AIDS or AIDS-related complex. alpha-Interferon A/D, which displays antiviral activity in mice, is a hybrid molecule composed of the N-terminal portion of human alpha-interferon A and the C-terminal portion of human alpha-interferon D. AZT and alpha-interferon A/D combination studies were conducted because in vitro studies of AZT and alpha-interferon have demonstrated that the combination is more effective in blocking HIV infection than either agent alone. Male and female B6C3F1 mice received AZT (approximately 98% pure) in 0.5% aqueous methylcellulose by gavage for 14 weeks or 2 years. In addition, male and female B6C3F1 mice received alpha-interferon A or alpha-interferon A/D by subcutaneous injection for 2 years, and male and female B6C3F1 mice received AZT in 0.5%% aqueous methylcellulose by gavage in combination with alpha-interferon A/D by subcutaneous injection for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow erythrocytes, and mouse peripheral blood erythrocytes. 14-WEEK AZT STUDY: Groups of 10 male and 10 female mice received AZT in 0.5% methylcellulose by gavage at doses of 0, 50, 100, 200, 800, or 2,000 mg/kg daily for 14 weeks. Additional groups of 10 male and 10 female mice received AZT in 0.5% methylcellulose by gavage at doses of 0, 100, 800, or 2,000 mg/kg daily for 14 weeks and then were held without treatment for an additional 4 weeks before necropsy. One female receiving 100 mg/kg and two females receiving 200 mg/kg died during week 1 as a result of gavage trauma; one female receiving 2,000 mg/kg also died prior to the end of the 14-week dosing period. One female receiving 2,000 mg/kg in the recovery study also died from gavage trauma during week 1. The final mean body weights of dosed mice were similar to those of the vehicle control groups at the end of the dosing period and at the end of the recovery period. Female mice receiving 200, 800, or 2,000 mg/kg gained less weight than the vehicle controls during the 14-week dosing period. Exposure to AZT was toxic to the bone marrow, resulting in significant changes in the peripheral blood (decreased hematocrit values, erythrocyte counts, and hemoglobin concentrations, and increased mean cell volume and mean cell hemoglobin) and bone marrow (erythroid hypoplasia) characteristic of a dose- and time-dependent, minimal to moderate, poorly regenerative macrocytic anemia. At the end of the 4-week recovery period, the hematology parameters had returned to normal, indicating that the hematotoxicity was reversible. 2-YEAR STUDIES: AZT Groups of 95 male and 95 female mice received AZT in 0.5% methylcellulose by gavage at daily doses of 0, 30, 60, or 120 mg/kg body weight, administered as two equal doses at least 6 hours apart, 5 days per week for 105 weeks. Each group of 95 animals was composed of a core group of 50 animals for evaluation of carcinogenic response, a group of 30 animals for evaluation of hematology and bone marrow cellularity, and a group of 15 animals from which blood was drawn for determination of plasma AZT concentrations at week 54. alpha-Interferon A/D and AZT/alpha-Interferon A/D Studies Groups of 80 male and 80 female mice received AZT in 0.5% aqueous methylcellulose by gavage at daily doses of 0, 30, 60, or 120 mg/kg body weight, given in two equal doses, 5 days per week for 105 weeks. Those groups receiving AZT also received sub-cutaneous injections of 500 or 5,000 U alpha-interferon A/D three times per week for 105 weeks. Additional groups of 80 male and 80 female mice received subcutaneous injections of the vehicle, 500 U alpha-interferon A/D, 5,000 Uutaneous injections of the vehicle, 500 U α-interferon A/D, 5,000 U α-interferon A/D, or 5,000 U α-interferon A, three times per week for 105 weeks. Each group of 80 animals was composed of a core group of 50 animals for evaluation of carcinogenic response and a group of 30 animals for evaluation of hematology and bone marrow cellularity. Because of the large number of animals involved, the 2-year studies were started in four phases and, for clarity, are presented as follows: the AZT study, the α-interferon A/D study, the AZT/500 U α-interferon A/D study, and the AZT/5,000 U α-interferon A/D study. Design of the 2-year AZT, AZT/α-Interferon A/D, and α-Interferon A/D Studies AZT Dose AZT Study AZT/500 U α-Interferon A/D Study AZT/5,000 U α-Interferon A/D Study 500 or 5,000 U α-Interferon A/D or 5,000 U α-Interferon A Study Vehicle Control 95 male and 95 female micea 80 male and 80 female miceb 80 male and 80 female miceb 80 male and 80 female miceb 30 mg/kg AZT 95 male and 95 female mice 80 male and 80 female mice 80 male and 80 female mice none 60 mg/kg AZT 95 male and 95 female mice 80 male and 80 female mice 80 male and 80 female mice none 120 mg/kg AZT 95 male and 95 female mice 80 male and 80 female mice 80 male and 80 female mice none aFor the AZT study, there were 95 male and 95 female mice; these were divided into 50 males and 50 females in the core groups, 30 males and 30 females in the clinical pathology groups (hematology and bone marrow analyses only), and 15 males and 15 females for plasma AZT concentration determinations. bFor the α-interferon A/D study and the AZT/α-interferon A/D studies, there were 80 male and 80 female mice for each study; these were divided into 50 males and 50 females in the core groups and 30 males and 30 females in the clinical pathology groups (hematology and bone marrow analyses only). Survival and Body Weights Survival and mean body weights of mice exposed to AZT, α-interferon A, α-interferon A/D, or AZT plus α-interferon A/D were generally similar to those of the vehicle control groups. Hematology and Bone Marrow Analyses All groups of male and female mice receiving AZT exhibited changes in peripheral blood and bone marrow characteristic of a dose- and time-dependent, minimal to mild, macrocytic, nonresponsive anemia. In females, these changes were evident throughout the study. In males, the macrocytic anemia had resolved by week 80 in the 30 mg/kg group; at study termination erythrocyte macrocytosis was present only in males receiving 60 or 120 mg/kg AZT or AZT plus α-interferon A/D. There were no treatment-related alterations in hematology or bone marrow parameters in groups that received only α-interferon A or A/D. Pathology Findings Incidences of squamous cell carcinoma and squamous cell papilloma or carcinoma (combined) of the vagina occurred with a positive trend and were significantly increased in groups of female mice receiving 60 or 120 mg/kg AZT alone or in combination with α-interferon A/D. Epithelial hyperplasia was observed in all dosed groups of females, and the incidence was significantly increased in the 120 mg/kg AZT group. Three renal tubule adenomas and one renal tubule carcinoma were observed in male mice receiving 120 mg/kg AZT; the combined incidence in this group exceeded the range in historical controls. A renal tubule adenoma was observed in one male receiving 60 mg AZT/kg and 500 U α-interferon A/D; how ever, none were observed in other groups. Evaluation of step sections revealed a few more renal tubule hyperplasias but no additional neoplasms. The incidence of harderian gland adenoma was increased in male mice receiving 120 mg/kg AZT and exceeded the range in historical controls. Harderian gland neoplasms were observed in other groups but did not follow a treatment-related pattern. Overall Incidences of Vaginal Neoplasms and Hyperplasia of the Vaginal Epithelium in Female Mice in the 2-Year Gavage Studies of AZT and AZT/α-Interferon A/Da Vehicle Control 30 mg AZT/kg 60 mg AZT/kg 120 mg AZT/kg AZT alone 2/197 (1&percnt;)b 1/197 0/49 (0&percnt;) 3/49 5/45 (11%&percnt;) 4/45 11/49 (22%&percnt;) 11/49 500 U α-Interferon A/D 0/49 (0%&percnt;) 0/49 0/44 (0&percnt;) 4/44 5/48 (10&percnt;) 8/48 6/48 (13&percnt;) 12/48 5,000 U α-Interferon A/D 1/50 (2&percnt;) 1/50 1/48 (2&percnt;) 4/48 5/48 (10&percnt;) 8/48 4/50 (8&percnt;) 15/50 aData are presented as number of vaginal neoplasms/number of animals microscopically examined (first line) and number of vaginal hyperplasias/number of animals microscopically examined (second line) bCombined incidences of controls from the AZT alone study and the AZT/α-interferon A/D studies; incidences in the vehicle control group from the AZT alone study are 0/50 (0%&percnt;) (neoplasms) and 0/50 (hyperplasia) Overall Incidence of Harderian Gland Neoplasms in Male Mice in the 2-Year Gavage Studies of AZT and AZT/α-Interferon A/Da Vehicle Control 30 mg AZT/kg 60 mg AZT/kg 120 mg AZT/kg AZT alone 13/200 (6%&percnt;)b 5/50 (10%&percnt;) 2/50 (4&percnt;) 10/50 (20%&percnt;) 500 U α-Interferon A/D 3/50 (6&percnt;) 3/50 (6&percnt;) 1/50 (2%&percnt;) 4/50 (8%&percnt;) 5,000 U α-Interferon A/D 3/50 (6&percnt;) 9/50 (18%&percnt;) 4/50 (8%&percnt;) 4/50 (8&percnt;) aData are presented as number of harderian gland neoplasms/number of animals necropsied bCombined incidences of controls from the AZT alone study and the AZT/α-interferon A/D studies; incidence in the vehicle control group from the AZT alone study is 3/50 (6&percnt;) Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms within the liver consistent with an infection with Helicobacter hepaticus. An organism compatible with H. hepaticus was confirmed by polymerase chain reaction-restriction fragment length polymorphism-based assays. Detection of dose-related differences in neoplasm incidences in these studies was not considered to have been significantly impacted by the infection with H. hepaticus or its associated hepatitis. GENETIC TOXICOLOGY: AZT is mutagenic in vitro and in vivo. It induced gene mutations in Salmonella typhimurium strain TA102, with and without S9; no increases in mutations were noted in the other tested strains of S. typhimurium. AZT induced sister chromatid exchanges, but not chromosomal aberrations, in cultured Chinese hamster ovary cells, with and without S9. In vivo studies with male mice administered AZT by gavage showed highly significant increases in micronucleated erythrocytes in bone marrow and peripheral blood after exposure periods that ranged from 72 hours to 14 weeks. CONCLUSIONS: Under the conditions of these 2-year gavage studies there was equivocal evidence of carcinogenic activity of AZT in male mice based on increased incidences of renal tubule and harderian gland neoplasms in groups receiving AZT alone. There was clear evidence of carcinogenic activity of AZT in female mice based on increased incidences of squamous cell neoplasms of the vagina in groups that received AZT alone or in combination with α-interferon A/D. Hematotoxicity occurred in all groups that received AZT. Treatment with AZT alone and AZT in combination with α-interferon A/D resulted in increased incidences of epithelial hyperplasia of the vagina in all dosed groups of females. Synonyms: AZT; 3'-azido-2',3'-dideoxythymidine; azidodeoxythymidine; azidothymidine; 3'-azidothymidine; 3'-deoxy-3'-azidothymidine; 3'-deoxy-(8CI) (9CI); BW A509U; Compound S; ZDV; zidovudine Trade name: Retrovir®
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PMID:NTP Toxicology and Carcinogenesis Studies of AZT (CAS No. 30516-87-1) and AZT/alpha-Interferon A/D B6C3F1 Mice (Gavage Studies). 1257 4

Chronic hepatitis C virus is a major worldwide cause of hepatitis, cirrhosis, end-stage liver disease, and hepatocellular carcinomas. Combination therapy of ribavirin with short- or long-acting interferon-alpha is now the standard treatment of chronic hepatitis C. This therapy is associated with a wide range of side effects. Although hemolysis is almost an invariable result of ribavirin, black urine due to hemoglobinuria has never been previously reported. We recently encountered two cases of black urine (hemoglobinuria) in patients treated with combination therapy. Based on reports of dark urine in many of our patients, we suggest that this phenomenon may be more common than is currently appreciated. It indicates a marked degree of hemolysis, which prompts immediate measurement of hemoglobin level.
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PMID:Hemoglobinuria with ribavirin treatment. 1264 48

The patient was a 47-year-old man who was diagnosed in 1989 as having chronic myelogenous leukemia (CML). He had been treated with interferon-alpha (IFN-alpha) and hydroxyurea. In August 1999, he was admitted to our hospital for examination of severe anemia and increased platelet count. On admission, his hemoglobin level was 6.3 g/dl, reticulocyte count was 0.7%, WBC count was 5,100/microliter, and platelet count was 57.3 x 10(4)/microliter. Bone marrow aspiration showed myeloid hyperplasia and near absence of erythroblasts. Bone marrow karyotype analysis showed a Ph chromosome with additional abnormalities. Pure red cell aplasia (PRCA) with accelerated-phase CML was considered. The IFN-alpha therapy was discontinued. Hydroxyurea at an increased dosage was effective in controlling the CML. In contrast, administration of cyclosporin A was not effective for the PRCA. The patient's condition was later complicated by acute hepatitis C virus infection. The IFN-alpha was restarted to control the CML and hepatitis. The patient remained erythroblastopenic and transfusion-dependent for more than 2 years. Association of CML and PRCA is rare. We discuss the mechanisms underlying PRCA occurring during the course of CML.
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PMID:[Pure red cell aplasia occurring during the course of chronic myelogenous leukemia]. 1499 37

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