Sequential 24-h urine samples were collected erectile dysfunction caused by hemorrhoids buy cheap cialis jelly 20mg online, and a subset was analysed for aflatoxin 8 1 metabolites erectile dysfunction onset trusted 20 mg cialis jelly. Aflatoxin M 1 was the main metabolite in all samples erectile dysfunction pump demonstration discount cialis jelly 20 mg with visa, accounting for 2-6% of the administered dose erectile dysfunction treatment natural remedies buy cialis jelly 20mg. Its excretion was greatly reduced (by 77%) when oltipraz was added to the diet erectile dysfunction in young males cialis jelly 20 mg for sale, but rapidly returned to control levels after cessation of the intervention erectile dysfunction studies cialis jelly 20mg sale. No such inhibition of aflatoxin M 1 excretion was seen in animals given oltipraz by gavage 24 h before dosing with aflatoxin 81 erectile dysfunction treatment vacuum constriction devices cheap 20 mg cialis jelly fast delivery. Thus can you get erectile dysfunction pills over the counter cialis jelly 20 mg line, four adult male marmosets were used as controls, four were given oltipraz, and three received ethoxyquin. On days 16-28, the treated animals received the synthetic dithiolthione oltipraz at 18 mg/kg bw per day or the antioxidant ethoxyquin at 30 mg/kg bw per day in their diet, whereas the control animals received the vehicles only. On day 26, each animal received a second dose of [3 H]aflatoxin B by gavage, and blood samples were drawn at 0, 2, 24, and 48 h. On day 28, the animals were killed, their livers were excised, and microsomal and cytosolic fractions were prepared. Twelve human liver samples were also obtained from the University of Washington, and the microsomal fractions were pooled. The oxidative metabolism of aflatoxin B was quantitatively similar in the two monkey species and in humans. In contrast to macaques, humans and marmosets lacked aflatoxin B glutathione conjugating activity. As the metabolism of aflatoxin B in marmosets resembled that in humans more closely than that in macaques, the focus of the study was on marmosets. Both oltipraz and ethoxyquin induced aflatoxin 81 -glutathione conjugating activity in the livers of some but not all marmosets. Other workers have demonstrated aflatoxin B-mercapturic acid in the urine of marmosets exposed to atlatoxin B1. Consistent with the results of the chemointervention trial in a human population (section 5. In a study of the inhibition of aflatoxin M1 production by bovine hepatocytes after intervention with oltipraz and another dithiolthione, 4-methyl-5-(2-pyrazinyl)-1,2dithiole-3-thione, oltipraz inhibited the metabolism of aflatoxin 81, as neither aflatoxin M1 nor aflatoxin B dihydrodiol (the second metabolite found in bovine hepatocytes) was formed. Although the authors proposed that oltipraz could be administered to dairy cows that had accidentally received aflatoxin B1 in their feed, unmetabolized aflatoxin 8 1 would still reach the systemic circulation. The drugs butylated hydroxyanisole, diethyl maleate, ethoxyquin, ~-naphtho flavone, oltipraz, phenobarbital, and trans-stilbene oxide were also investigated. In a long-term intervention study with coumarin to study tumour formation, six groups of eight 12-week-old male Fischer 344 rats were given the same diets described above but were placed on diets containing coumarin and aflatoxin 8 1 for 24 weeks before being transferred to a control diet from week 25 until termination of the experiment at week 50. Microsomal and cytosolic fractions were prepared from fresh liver or from samples snap-frozen in liquid nitrogen. To assess the biological significance of enzyme induction by dietary coumarin, two intervention studies were performed, in which the ability of benzopyrone to inhibit aflatoxin 8 1-initiated preneoplastic nodules (at 13 weeks) or aflatoxin 8 1-initiated liver tumours (at 50 weeks) was investigated. Pretreatment with coumarin for 2 weeks before administration of aflatoxin 8 1 and continued treatment during exposure to the carcinogen for a further 11 weeks protected the animals completely from development of hepatic preneoplastic lesions by 13 weeks. Treatment with coumarin in a longer-term dietary intervention, before and during exposure to aflatoxin 8 1 for 24 weeks, resulted in significant inhibition of the number and size of tumours that developed by 50 weeks. The authors concluded that consumption of a coumarincontaining diet provides substantial protection against the initiation of hepatocarcinogenesis by aflatoxin 81 in rats. The other phytochemicals and synthetic drugs tested in this study induced different zone- and sex-specific enzymes in the liver. The complexity of gene-environment interactions is emphasized by the fact that certain inducing agents can cause nuclear translocation of drug-metabolizing enzymes (Kelly et al. Histopathological examination showed liver lesions similar to those caused by aflatoxin 8 1 and necrosis of the renal tubules. Milk naturally contaminated with aflatoxin M1produced fewer lesions than artificially contaminated milk, however, suggesting differences in the bioavailability of naturally and artificially occurring aflatoxin M1. Studies on the acute toxicity of aflatoxins in 1day-old ducklings suggest that aflatoxin M1 and aflatoxin 8 1 act by a similar mechanism in causing acute toxicity and subcellular alterations, such as changes in liver parenchymal cells, dissociation of ribosomes from the rough endoplasmic reticulum, and proliferation of the smooth endoplasmic reticulum, and that only the naturally occurring isomer of each aflatoxin is biologically active. Female trout with aflatoxin Mi-induced hepatomas had a significantly higher mortality rate at maturation (16-20 months) than males. The author concluded that aflatoxin M 1 is a potent liver carcinogen but less potent than aflatoxin 8 1. Degeneration of the liver was seen in all three groups and in the control group, but no tumours or preneoplastic changes were found. The investigators concluded that differences in trout strain could have contributed to the differences between their results and those of Sinnhuber, but that aflatoxin M1 is less carcinogenic in trout than aflatoxin 8 1. A second group of rats was given natural aflatoxin 8 1 at the same concentration and under similar conditions. Only one rat (3%) given aflatoxin M1 developed a hepatocellular carcinoma, whereas 28% had liver lesions (preneoplastic lesions). The authors suggested that the greater polarity of aflatoxin M1 than aflatoxin 8 1 might be associated with the higher incidence of intestinal tumours. It was concluded that aflatoxin M1 was a hepatic carcinogen, but with a potency 2-10% that of aflatoxin 8 1 (Cullen et al. This study is the one usually cited in comparisons of the carcinogenicity of atlatoxin 8 1 and aflatoxin M. In the wing spot test, in which larval flies trans-heterozygous for the somatic cell markers mwh and flr3 were treated and the wings were inspected at adulthood for spots manifesting the phenotypes of the marker, the genotoxicity of aflatoxin M 1 and aflatoxin B 1was similar. The authors concluded that aflatoxin M 1 is genotoxic in mammalian systems in vivo (Shibahara et al. One week before administration of aflatoxin B1, one group also received oltipraz at 0. Samples of 1 ml of blood and 24-h urine were obtained from each animal at weekly intervals. As measured in a single cross-sectional analysis at the end of treatment with aflatoxin 8 1, oltipraz decreased the urinary aflatoxin-N7-guanine content by 93%. The tree shrew model is useful and may allow determination of whether agents such as oltipraz sustain their chemopreventive effect against aflatoxin in the presence of chronic infection with H8V (Li et al. The rats were then separated into groups fed a methyl-sufficient or -deficient diet ad libitum or with dietary restriction. Dietary restriction reduced hepatic-cell proliferation, while the methyl-deficient diet and aflatoxin B1 pretreatment increased cell proliferation. Telomerase activity was decreased by dietary restriction and increased by the methyl-deficient diet and aflatoxin 8 1 pretreatment. These results are consistent with a role of telomerase in hepatocarcinogenesis, although the origin of the cells giving rise to the increase in telomerase activity was not determined (Chou et al. Seven of 1O animals fed no ascorbic acid died within 73 h of administration of aflatoxin 8 1, and their livers showed massive regional necrosis and multilobular degeneration. None of the animals given 25 mg/day ascorbic acid died, but their livers showed changes similar to those seen in the group that received no ascorbic acid. None of the animals given 300 mg/day of ascorbic acid died or had pathological changes in the liver, and their alanine and aspartate aminotransferase activities were unaffected. Production of aflatoxin M1 by liver microsomes tended to be higher than that in the other two groups. One animal died, and the livers of all animals showed centrilobular degeneration and moderate necrosis in scattered hepatocytes. The results indicate that intake of 300 mg of ascorbic acid virtually protected the animals from the acute toxicity of aflatoxin 8 1 given by gavage but not when administered as a second dose intraperitoneally (Netke et al. The authors concluded that these carotenoids exert their protective effect by deviating aflatoxin 8 1 metabolism towards detoxication pathways. Its protective effect against the initiation of liver preneoplastic foci by aflatoxin 81 appears to be mediated by other mechanisms (Gradelet et al. The hepatotoxicity of aflatoxin 81 is augmented by bacterial endotoxin lipopolysaccharide in rats. Male Sprague-Dawley rats were given aflatoxin 8 1 at 1 mg/kg bw or the vehicle, 0. Liver injury was assessed 6, 12, 24, 48, 72, or 96 h after administration of aflatoxin 81. Histological examination of liver sections and measurements of alanine and aspartate aminotransferase activity in serum were used to evaluate hepatic parenchymal-cell injury. No or little injury was seen in rats treated with aflatoxin 81 or lipopolysaccharide alone, but hepatic parenchymal-cell injury was pronounced by 24 h in the group treated with aflatoxin 8 1 and lipopolysaccharide, returning to control values by 72 h. Changes in serum markers indicative of biliary-tract alterations were evident by 12 h, but the values had returned to control levels by 72 h. The nature of the hepatic lesions suggested that lipopolysaccharide potentiated the effects of aflatoxin 8 1 on both parenchymal and bile-duct epithelial cells. The authors suggested that the results of this study might partly explain the severity of human cases of acute aflatoxicosis. In addition, persons with hepatitis who have an inflammatory response may be predisposed to the carcinogenic effects of aflatoxin 8 1, as the results of this study suggest that inflammation accompanied by hepatic parenchymal-cell hyperplasia might contribute epigenetically to aflatoxin B-induced carcinogenesis by promoting tumour formation (Barton et al. Aflatoxins are among the most toxic of the known mycotoxins and have been implicated in the deaths of humans and animals that have consumed mouldy food. Whife the liver is the target organ for aflatoxicosis, aflatoxins are also found in other aninial tissues and products, such as meat, milk, and eggs. As mature animals modify ~nd eliminate toxins effectively, however, the main concern is long-term intake of concentrations of these toxins, which can lead to cancer and immunosuppression. Although intake of low doses of aflatoxins may not cause death or tissue damagd it may severely affect the cost-effectiveness of animal production. Sensitivity to aflatoxins varies from1one species to another, and, within the same species, the severity of toxicity depends on dose, duration of intake, age, and breed of the animals, and their dietary proteif content. In general, ingestion of aflatoxin re~ults in a variety of clinical signs which depend on the amount consumed and the sp1ecies and age of the animal. Aflatoxin may make an animal more susceptible to infectious diseases by impairing its immune system or potentiating a bacterial infetuon. Intake of aflatoxins during gestation may affect offspring as well as adults (Mille~ & Wilson, 1994). The carry-over of aflatoxin from animal feed to milk and tissue is discussed in section 8. The epidemiological studies to date have focused on aflatoxin B 1; ingestion of aflatoxin M 1 with milk and milk products has not been directly related to liver cancer. Some of the epidemiological observations that implicate aflatoxins in the etiology of liver cancer derive from observations of unusual clusters of disease or unexplained trends in incidence. Additional indications are provided by the results of case-control and cohort studies based on adequate technique~~(and comprehensive evaluation of the risk factors in the etiology of liver cancer. The age-specific curves showed a shift towards liver cancer among persons aged 40-60. The authors discuss in detail and quite convincingly the factors that interfere in analyses of time trends for liver cancer, including the widespread introduction of new diagnostic means (ultrasound, a-fetoprotein analysis), improved registration practices (histological confirmation and coding), and the quality of analysis (trend and birth-cohort analyses}. Also in Japan, a report on trends in death from liver cancer showed that alcohol was the agent primarily responsible. Other surrogate measures used were the incidence of oesophageal cancer and the mortality rate from cirrhosis (Makimoto & Higuchi, 1999). Table 3 shows current estimates of the attributable fractions for the main risk factors associated with liver cancer. The attributable fractions do not necessarily add up to 100% because of multiple exposures and possible interactions between risk factors. In Fusui County, primary liver cancer was correlated to intake of aflatoxin 8 1 but not aflatoxin, M1 and the decreasing trend in the aflatoxin-albumin adducts over time in Fusui were attributed to improved agricultural practices (Yu et al. Subjects were categorized as having a low or a high intake of aflatoxin 8 1 and were dichotomized around the population mean of aflatoxin-albumin adducts. The amounts of aflatoxin 81 measured were comparable with those in previous year-long studies in this population. A small case-control study in the Sudan showed a relationship between grain storage conditions and the aflatoxin contamination of peanuts, and some association between storage conditions and the occurrence of liver cancer (Omer et al. At the beginning of the study, 54% of the subjects had aflatoxin M1 in their urine; 22 subsequently developed hepatocellular carcinoma. All four patients with hepatocellular carcinoma who had aflatoxin M1 in their urine and who were tested for mutations in the P53 oncogeneshowed the missense mutation in codon 249. The levels of biomarkers of aflatoxin in urine differed somewhat between cases and controls. A trend to increased risk with urinary aflatoxin M1 was reported, but the numbers were too small to ensure proper power. A small case-control study was conducted among black Africans to determine the effect of iron overload and other environmental factors on the risk for hepatocellular carcinoma. The evidence is not entirely consistent, and the study from southern Africa found no significant association berween the presence of aflatoxin-albumin adducts in serum and liver cancer. Other cohort studies gave conflicting results with regard to the role of aflatoxin in the etiology of liver cancer. The cohorts were selected to examine why the estimated risk for liver cancer in some areas of China was significantly higher (two- to threefold) than that on the west coast of Africa. It has been hypothesized that metabolic polymorphisms of the genes that regulate the metabolism of aflatoxins could explain the established interspecies differences in susceptibility to aflatoxininduced carcinogenicity and the largely hypothetical differences in susceptibility among human groups. Some epidemiological studies have addressed the environmental factors that may modulate the natural history of aflatoxins and biomarkers of aflatoxins under various conditions of exposure. The major determinants of the amounts of aflatoxin in blood were place of residence and season. Understanding the natural history of the biomarkers used in epidemiological studies is an absolute requirement for proper interpretation of much of the available literature. In a study in Taiwan, aflatoxin B 1-N7-guanine adducts were measured in urine as a function of the hormonal and nutritional parameters that may affect aflatoxin adduct formation. This study is significant in that it indicates some of the environmental and host determinants of adduct formation for use in etiological studies (Yu et al. Nutritional determinants of adduct formation, if validated, should be treated as confounders in epidemiological studies in which urinary adducts are used as a biomarker. The tests show defects in predisposition to chromosome breakage or the capacity to repair chromatid breaks or both. The results suggest that individual susceptibility can be important in determining the outcome in exposed individuals. No epidemiological studies have been reported in which host factors determined by these methods were adjusted for (Wu et al. The proportion of babies born to highly infectious mothers who also became carriers decreased from 86-96% to 12-14%. The average annual incidence of hepatocellular carcinoma in children aged 6-14 decreased significantly from 0. Cases of liver cancer were ascertained by record linkage and from medical records covering 1986-89. A multivariate loglinear model was used to test for statistical significance and to estimate relative risks. The follow-up period represented 1 404 566 person-years (average, 3 years and 1O months), and 302 cases were ascertained, to give an overall incidence rate of liver cancer of 22 per 100 000 person-years. The relative risk for primary liver cancer was18% (95% confidence interval, 14-23) among chronically infected men, 0. In China, some 40% of carriers of H8V were infected by perinatal transmission from their mothers. The effectiveness of vaccination has been reported to be 70% in some areas of China and as much as 90% in others. In Africa, introduction of the vaccine into the routine programme for infant vaccination reduced the carriage rate by 94%.
The rate of disappearance of ochratoxin A was slower from blood than from kidney erectile dysfunction cialis purchase 20mg cialis jelly with amex, liver vasculogenic erectile dysfunction causes purchase 20mg cialis jelly with mastercard, and other tissues in pigs (Hult et al erectile dysfunction 30s buy cheap cialis jelly 20 mg online. In a similar experiment in rats erectile dysfunction fruit order cialis jelly 20 mg on-line, the distribution after 24 h was greatest in lung and erectile dysfunction pills at gnc discount 20 mg cialis jelly otc, in decreasing order erectile dysfunction fact sheet buy cialis jelly 20 mg line, in adrenal medulla erectile dysfunction causes psychological order cialis jelly 20 mg fast delivery, skin erectile dysfunction statistics us generic 20 mg cialis jelly overnight delivery, liver, myocardium, kidney, salivary gland, adrenal cortex, muscle, gastric mucosa, and bone marrow (Breitholtz-Emanuelsson et al. The tissue distribution in pigs, rats, chickens, and goats generally followed the order kidney > liver> muscle> fat (Harwig et al. In another study, it was found in eggs when the birds were fed 10 mg/kg bw (Juszkiewicz et al. Egg-laying Japanese quail were given a single oral dose of 0, 1, 5, or 20 mg/ kg bw. The toxin was still present in abdominal yolks 4 days after administration, and the mean concentration was 10-fold higher than in whole eggs. No ochratoxin A was found in eggs of birds given 1 mg/kg bw (Piskorska-Pliszczynska & Juszkiewicz, 1990). At 72 h, the suckling pups had higher concentrations of ochratoxin A than their dams in both blood and kidney (Breitholtz-Emanuelsson et al. Whole-body autoradiography after intravenous administration of high doses of [1 4 C]ochratoxin A showed that it could cross the placenta more readily when given on days 8 and 9 than day 1O of gestation, with radiolabel appearing within 20 min in the uterine wall, placenta, and fetal tissues. Ochratoxin A given to mice on day 17 of gestation resulted in very little radiolabel in fetuses (Appelgren & Arora, 1983a,b). Differences in fetal uptake of ochratoxin A at different times during gestation were suggested to be due to differences in the placenta, which was considered to be completely developed by day 9 of gestation. After intraperitoneal injection of ochratoxin A on day 11 or 13 of gestation, residues appeared more slowly and reached maximum values 30-48 h after dosing. The concentrations in the placenta were high 2-6 h after injection and then decreased more slowly than from other tissues. The serum half-life of ochratoxin A was 29 hat day 11 and 24 hat day 13 of gestation. Pups from ochratoxin A-treated dams were cross-fostered at birth to control dams and vice versa. Treatment did not affect maternal body weight nor alter the birthweight or development of pups. The concentrations of ochratoxin A in the blood and kidney of exposed pups were three to four times higher than those in the dams. No differences in weight gain or in body or kidney weight were seen between pups exposed in utero, via lactation, or both. The transfer of ochratoxin A to milk was very efficient (60% of the blood concentration at 8 weeks). The highest blood and kidney concentrations were found in offspring exposed in utero and via milk, but the most significant exposure was via milk (Hallen et al. After subcutaneous administration of [3H]ochratoxin A to rats on day 12 of gestation, fetal uptake was delayed, with maximum concentrations 48-72 h after dosing, representing about 0. The toxin was effectively transported from blood to milk and subsequently to the offspring. Higher concentrations were found in maternal plasma than in milk, and a linear relationship was found between the concentrations in milk and plasma of offspring. The plasma:kidney concentrations were much higher in offspring than in adults, perhaps due to slower detoxication in the former (Ferrufino-Guardia et al. In a more recent study, however, ochratoxin A was transmitted to six piglets in utero when the sow was fed naturally contaminated feed; the blood concentrations in the newborn piglets were 0. Thus, in rats, both the urinary and faecal excretory routes are important, the relative contribution of each depending on factors such as route of administration and dose (Kuiper-Goodman & Scott, 1989). In all species, the relative contribution of each excretory route is also influenced by the degree of serum macromolecular binding and differences in the degree of enterohepatic recirculation of ochratoxin A (Hagelberg et al. Up to 33% of the radiolabel on an orally administered dose of ochratoxin A was excreted into the bile of rats up to 6 h after dosing; only trace amounts of ochratoxin a. Biliary excretion of ochratoxin A was increased and urinary excretion of ochratoxin A and ochratoxin a. When ochratoxin A was administered to rats intraperitoneally, only traces of ochratoxin A and ochratoxin a. In pre-ruminant and ruminant calves, 85-90% of orally administered ochratoxin A was excreted as ochratoxin a. In rats, detoxication by hydrolysis to ochratoxin a is a function of the bacterial microflora of the caecum (Galtier, 1978). The enzymes responsible for hydrolysis to ochratoxin a in cows and rodents are carboxypeptidase A and chymotrypsin (Pitout, 1969a,b; Pitout & Nel, 1969). Inhibition of the flora of the lower gastrointestinal tract of rats by neomycin reduced hydrolysis of ochratoxin A to ochratoxin a. Studies with rat tissue homogenate showed that the duodenum, ileum, and pancreas also have a high capacity to carry out this reaction, whereas the activity in the liver and kidney was low (Suzuki et al. In rats given [14C]ochratoxin A, most of the radiolabel was attached to ochratoxin A, indicating that efficient metabolism of this toxin is lacking in most tissues other than the intestine (Galtier et al. Incubation of the contents of the four stomachs of cows indicated effective hydrolysis of ochratoxin A to ochratoxin a. Assuming a similar reaction velocity in vivo, it was estimated that up to 12 mg/kg of feed could be degraded (Hult et al. Sheep also have a good capacity to detoxify ochratoxin A before it reaches the blood (Kiessling et al. Studies in mice suggest that ochratoxin A circulates from the liver into the bile and into the intestine, where it is hydrolysed to ochratoxin a (Moroi et al. About 25-27% of ochratoxin A, given either intraperitoneally or orally to rats, was present as ochratoxin a in the urine. Its presence in the urine can be explained by reabsorption from the intestine (Storen et al. A similar mechanism of intestinal reabsorption of ochratoxin a has been suggested to occur in ruminant calves (Sreemannarayana et al. Other minor urinary metabolites of ochratoxin A are 4-0H (4R-and 4S) epimers produced in rat and rabbit liver (St0rmer et al. Ochratoxin C, a metabolite of ochratoxin A produced in rumenal fluid, is as toxic as ochratoxin A (cited by Galtier et al. Ochratoxin B, a dechloro derivative of ochratoxin A, may occur with ochratoxin A in cereal products. In rats, it is less toxic than ochratoxin A and is metabolized to 4-0Hochratoxin Band ochratoxin ~ (St0rmer et al. Many researchers consider that the toxicity of ochratoxin A is due to one of its metabolites. The studies cited above indicate, however, that, in rats, ochratoxin A itself, rather than one of its metabolites, is the active toxic agent, since the known metabolites are less toxic than or as toxic as ochratoxin A. With phenobarbital, the difference was smaller 144 h after dosing with ochratoxin A than at 48 h. In contrast, preliminary studies in mice showed that simultaneous feeding of phenobarbital slightly increased the incidence of liver tumours seen with ochratoxin A alone, and that the mice developed large, multiple hepatomas (Suzuki et al. It has been suggested that it has a long serum half-life, on the basis of its strong binding to human serum macromolecules (Bauer & Gareis, 1987; Hagelberg et al. The diabetogenic effect of ochratoxin A was thought to be due to inhibited synthesis and/or release of insulin from pancreatic cells, thereby suppressing glycolysis and glycogenesis and enhancing gluconeogenesis and glycogenolysis (Subramanian et al. An increase in renal endoplasmic reticulum calcium pump activity was observed, suggesting an association with ochratoxin A-induced renal cytotoxicity (Rahimtula & Chong, 1991). The biochemistry and molecular aspects of the action of ochratoxin A in both prokaryotes and eukaryotes have been reviewed (Roschenthaler et al. The findings are inconsistent, owing to differences and limitations in experimental models and procedures as well as interfering factors, especially in more complex organisms. In prokaryotes (Konrad & Roschenthaler, 1977), eukaryotic microorganisms (Creppy et al. The inhibition of protein synthesis is specific and occurs at the post-transcriptional level, ochratoxin A having a direct effect on the translation step in protein synthesis. In this reaction ochratoxin A may be regarded as an analogue of phenylalanine, and in cell cultures the competitive inhibition could be reversed by an increase in phenylalanine concentration (Creppy et al. The concentration of ochratoxin A inside hepatoma cells was 200- to 300-fold that in the medium (Creppy et al. A dose-related inhibition of protein synthesis was found in mice given ochratoxin A intraperitoneally at a dose~ 1 mg/kg bw. Ochratoxin A may also act on other enzymes that use phenylalanine as a substrate, although no direct effect on the activity of other isolated enzyme systems has been demonstrated (Roschenthaler et al. In kidney slices from rats 2 days after they had been fed ochratoxin A at 2 mg/kg bw, the activity of renal phosphoenolpyruvate carboxykinase, a key enzyme in the gluconeogenic pathway, was lowered by 50% (Meisner & Krogh, 1986). The effect of ochratoxin A on phenylalanine metabolism was studied in isolated hepatocytes and in liver homogenates from male rats treated in vivo. Both the hydroxylation of phenylalanine to tyrosine and the subsequent metabolism of tyrosine, as measured by homogenate oxidation, were inhibited when ochratoxin A at a concentration of 0. It was suggested that ochratoxin A stimulates lipid peroxidation by complexing Fe3+ and facilitating its reduction. Subsequent to oxygen binding, an iron-oxygen complex initiates lipid peroxidation. Cytochrome P450, free active oxygen species, and free hydroxy radicals do not appear to be involved in Fe3+-ochratoxin A- stimulated lipid peroxidation. Oral administration of ochratoxin A at 6 mg/kg bw to rats appeared to increase lipid peroxidation in vivo, causing a sevenfold increase in ethane exhalation (Rahimtula et al. In pig renal cortical tissue, ochratoxin Aand citrinin added singly or in combination at a concentration of 1o-s or 10-3 mol/L did not elicit consistent or strong synergistic effects, as measured by transport of tetraethylammonium and paraaminohippurate ions, or protein synthesis measured with l3 H]leucine (Braunberg et al. The effects of superoxide dismutase and catalase on ochratoxin A-induced nephrotoxicity were studied. Superoxide removes oxygen by converting it to hydrogen peroxide; this enzyme works in conjunction with catalase, which removes hydrogen peroxide within cells. Superoxide dismutase and catalase prevented most of the nephrotoxic effects induced by ochratoxin A, observed as enzymuria, proteinuria, and creatinaemia, and increased the urinary excretion of ochratoxin A. The results indicated that superoxide radicals and hydrogen peroxide are likely to be involved in the nephrotoxic effects of ochratoxin A in vivo (Baudrimont et al. In addition, ochratoxin A blocked membrane anion conductance in canine kidney cells in vitro (Gekle et al. Dogs and pigs were the most sensitive species and rats and mice the least sensitive. As is the case with many xenobiotics, neonatal rats were considerably more susceptible than adults. Histopathological and electron microscopic studies were conducted with groups of 1O male Long-Evans and Sprague-Dawley rats given benzene-free ochratoxin A at a single dose of 0, 17, or 22 mg/kg bw in 0. The earliest changes were multifocal haemorrhages in many organs and fibrin thrombi in the spleen, the choroid plexus of the brain, liver, kidney and heart, suggesting disseminated intravascular coagulation. The effect was postulated by the authors to be due to activation of extrinsic and intrinsic systems of coagulation. Other changes were hepatic and lymphoid necrosis, enteritis with villous atrophy, affecting the jejunum most severely, and nephrosis. The myocardial changes were considered to be related to shock and subsequent ischaemic injuries (Albassam et al. Results of short-term studies of the toxicity of ochratoxin A Species, strain, sex, age No. At the two higher doses, growth retardation, reduced food consumption, and increased serum urea nitrogen were seen. Renal lesions, involving degenerative changes in the entire tubular system, and a decrease in urine volume were seen at all doses. Increased eosinophilia and karyomegaly in cells of the proximal convoluted tubules were noted at all doses (Munro et al. At that time, eight animals from each group were killed, and the remaining rats were fed control diet for an additional 90 days. No changes in blood urea nitrogen or urinary or haematological parameters were seen at any dose. After 90 days at the two higher dietary concentrations, the relative kidney weights were reduced in animals of each sex; these had returned to control values after the 90-day recovery period, except in males at the highest dose. Dose-related changes in morphological appearance were seen after 90 days of treatment at doses;::: 0. In animals at the highest dose that were subsequently given control diet for 90 days, the karyomegaly and tubular basement membrane thickening persisted, but otherwise the kidneys appeared normal (Munro et al. Similar effects were seen when ochratoxin A was administered to groups of four to six adult Sprague-Dawley and Wistar rats by intraperitoneal injection for 57 days at a dose of 0, 0. Decreased body weight, increased urine flow, increased urinary protein, increased urinary glucose, and impaired urinary transport of organic substances were seen at all doses. SpragueDawley rats were more sensitive than Wistar rats, and males were more sensitive than females. It was suggested that the increased urinary protein indicated interference with protein reabsorption by cells of the convoluted tubules (Berndt & Hayes, 1979). Ochratoxin A was administered by gavage in maize oil to groups of five weanling male and female Fischer 344/N rats at a dose of 0, 1, 4, or 16 mg/kg bw per day on 5 days per week for a total of 12 doses over 16 days. All rats that received the highest dose had diarrhoea and nasal discharge and died before the end of the study. Increased relative weights of kidneys, heart, and brain, thymus atrophy, forestomach necrosis and/or hyperplasia, and haemorrhage of adrenal glands were seen at the two higher doses. Bone-marrow hypoplasia and nephropathy were seen at all doses, involving renal tubular degenerative and regenerative changes (National Toxicology Program, 1989). Growth retardation and a reduced relative kidney weight were seen in males at the two higher doses. Milder renal changes consisting of tubular atrophy were seen at lower doses (National Toxicology Program, 1989). Blood samples from fasted treated rats contained about twice the amount of glucose as those of controls. In a glucose tolerance test, the insulin concentration did not reach that in control rats. Total carbohydrate and glycogen concentrations in liver of treated rats were reduced, as seen earlier (Suzuki et al. No changes were observed in renal function, but tubular necrosis and ultrastructural changes in the proximal tubules were observed at all doses. Necrosis of lymphoid tissues of the thymus and tonsils was also seen at all doses (Kitchen et al. Decreased renal function, nephropathy, and reduced renal enzyme activity were reported. Progressive nephropathy but no renal failure was seen in female pigs given feed containing 1 mg/kg for 2 years; no results were reported for male pigs (Krogh & Elling, 1977; Elling, 1979a,b, 1983; Elling et al. Of the nine surviving treated mice, five had hepatic-cell tumours, nine had renal cystic adenomas, and two had solid renal-cell tumours (terms used by the authors). It was not clear indicated whether the liver tumours were benign or malignant (Kanisawa & Suzuki, 1978). In a second study from the same laboratory, diets containing ochratoxin A at O or 25 mg/kg, equivalent to 3. All 20 surviving treated mice had renal cystic adenomas, six had solid renal tumours, and eight had hepatic-cell tumours. In a third study from the same laboratory, the mice were not exposed for life but for 70 weeks. Diets containing ochratoxin A at 0 or 50 mg/kg, equivalent to 7 mg/kg bw per day, were fed to groups of 16 adult male ddY mice for 5-30 weeks, followed by control diet for 40-65 weeks. No renal or liver tumours were observed in control mice or in mice fed ochratoxin A for:::; 10 weeks. The incidences of renal-cell tumours were 3/15, 1/14, 2/15, and 4/17 after 15, 20, 25, and 30 weeks on the ochratoxin Acontaining diet, respectively. A significant increase in the incidence of liver tumours was observed after mice had been fed ochratoxin A for 25 weeks (5/15) or 30 weeks (6/17). These results indicated that the renal and liver tumours persisted through subsequent feeding of control diet (Kanisawa, 1984). In these studies, two types of renal tumour were distinguished by the authors: papillary cyst adenomas (benign) and solid renal-cell tumours, which contained atypical cells, displayed infiltrative growth, and were interpreted by the Committee as malignant. Preneoplastic renal lesions were frequent and multiple and consisted of distended tubules with atypical epithelial cells.
Graves disease is marked by goiter (enlarged thyroid gland) drugs for erectile dysfunction generic 20mg cialis jelly fast delivery, thyroid bruit erectile dysfunction or gay cheap cialis jelly 20mg otc, hyperthyroidism erectile dysfunction most effective treatment cheap cialis jelly 20mg fast delivery, ophthalmopathy zyrtec impotence purchase cialis jelly 20mg with amex, and dermopathy erectile dysfunction drug approved to treat bph symptoms effective 20 mg cialis jelly. Ophthalmopathy is characterized by inflammation of extraocular muscles erectile dysfunction caused by diabetes discount 20 mg cialis jelly with amex, orbital fat erectile dysfunction dx code cialis jelly 20 mg on line, and connective tissue impotence vs infertile buy cheap cialis jelly 20 mg line, resulting in proptosis (exophthalmos), sometimes with impairment of eye muscle function (diplopia), and periorbital edema. Graves dermopathy is characterized by raised hyperpigmented orange peel texture papules. The degree of elevation of serum-free T4 and free T3 levels can give an estimate of the severity of the disease. Treatment options for Graves disease are medications, radioactive iodine, or surgery. The antithyroid drugs work mainly by decreasing the production of thyroid hormone. They can be used for short-term (prior to treatment with radioactive iodine or surgery) or long-term (1-2 years) treatment, after which the chance for remission is 20% to 30%. Possible side effects are rash, allergic reactions, arthritis, hepatitis, and agranulocytosis. It is administered as an oral solution of sodium 131I that is rapidly concentrated in thyroid tissue, inducing damage that results in ablation of the thyroid, depending on the dose, within 6 to 18 weeks. Radioactive iodine is contraindicated in pregnancy, and women of reproductive age are advised to postpone pregnancy for 6 to 12 months after treatment. Graves ophthalmopathy might be exacerbated by radioactive iodine treatment, so glucocorticoids can be used to prevent this in selected patients. Subtotal thyroidectomy usually is reserved for large goiters with obstructive symptoms (dyspnea, dysphagia). Possible complications include laryngeal nerve injury and hypoparathyroidism (due to removal of parathyroids or compromise of the vascular supply to them). For our patient, treatment with radioactive iodine or antithyroid medications seems the most reasonable way to proceed, and a discussion regarding her options and our recommendations should take place after the diagnosis is confirmed. Other causes of thyrotoxicosis include the following: Toxic multinodular goiter: Found mainly in elderly and middle-age patients. Radioactive iodine uptake is normal to increased, and the scan reveals irregular thyroid lobes and a heterogeneous pattern. Autonomous hyperfunctioning adenoma ("hot nodule" or Plummer disease): Hyperthyroidism usually is not present unless the nodule is more than 3 cm. The iodine scan looks like the flag of Japan: it demonstrates the hot nodule as having increased uptake (dark) and the rest of the gland with suppressed uptake (white). Cold nodules (no increased thyroid hormone production and no demonstration of local uptake if thyroid scan is performed) have a 5% to 10% risk of malignancy, so fine-needle aspiration, surgical removal, or ultrasonographic follow-up is needed for these nodules. Thyroiditis: Caused by destruction of thyroid tissue and release of preformed hormone from the colloid space. Subacute (de Quervain) thyroiditis is an inflammatory viral illness with thyroid pain and tenderness. The hyperthyroid phase lasts for several weeks to months, followed by recovery, but some patients will then develop hypothyroidism. Treatment with nonsteroidal anti-inflammatory medications and beta-blockers usually is sufficient, but in severe cases, glucocorticoids might be used. Other forms include postradiation, postpartum, subacute (painless thyroiditis), and amiodarone-induced thyroiditis. Medications: Excessive ingestion of thyroid hormone (factitious or iatrogenic), amiodarone, and iodine load. It often includes the thyroid gland features described, as well as the distinctive eye findings. Thyroid storm is an exaggeration of hyperthyroid features with extreme tachycardia (heart rate >140 bpm), fever, and central nervous system dysfunction, such as confusion or coma. In patients with Graves disease, thyrotoxic symptoms may be treated with antithyroid medication or by thyroid gland ablation by radioactive iodine or surgery, but the ophthalmopathy may not improve. Graves disease may remit and relapse; in patients treated medically, one-third to half will become asymptomatic within 1-2 years. After radioablation, most patients with Graves disease become hypothyroid and will require thyroid hormone supplementation. Hyperfunctioning thyroid nodules (excessive thyroid hormone production, suppressed thyroid-stimulating hormone, "hot" on radionuclide scan) almost never are malignant. Most "cold" thyroid nodules are not malignant, but fine-needle aspiration should be used to evaluate the need for surgical excision. However, the fever has not abated, and she still experiences left-sided chest pain, which is worse when she coughs or takes a deep breath. In addition, she has started to feel short of breath when she walks around the house. Physical examination is significant for decreased breath sounds in the lower half of the left lung fields posteriorly, with dullness to percussion about halfway up. There are a few inspiratory crackles in the mid-lung fields, and her right side is clear to auscultation. She has diminished breath sounds and dullness to percussion on the left side of her chest, suggesting a large left-sided pleural effusion, which is confirmed by chest radiography. The effusion likely is caused by infection in the adjacent lung parenchyma and may be the cause of her failure to improve on antibiotics. Understand the use of Light criteria to distinguish transudative effusions from exudative effusions, as a guide to the etiology of the effusion. Learn what pleural fluid characteristics suggest a complicated parapneumonic effusion or empyema, and the need for drainage. Know the treatment of a complicated parapneumonic effusion that does not improve after thoracentesis. Considerations In this patient, the effusion is large, and if it is free-flowing, which would be evaluated with a lateral decubitus film, then diagnostic thoracentesis can easily be accomplished. It is important to determine if the effusion is, in fact, caused by the pneumonia, and, if so, whether it is likely to resolve with antibiotics alone or will require drainage with tube thoracostomy. Approximately 50 mL of fluid is needed in order to be visible on a lateral decubitus film (more reliable in detecting smaller effusions), and fluid volume more than 500 mL usually obscures the whole hemidiaphragm. With removal of more fluid, the patient is at risk for developing reexpansion pulmonary edema. Transudate Versus Exudate To appreciate the pathophysiology of the formation of a transudate versus an exudate is to understand the differential under each category. Approximately 10 mL of pleural fluid is formed every day by the visceral pleura and absorbed by the parietal pleura (capillaries and lymphatics). Less commonly, impaired lymphatic drainage, as occurs in chylothorax, or lymphangitic spread of a malignancy may cause an exudative fluid. For a fluid to be labeled an exudate, it must meet at least one of the following criteria (transudates meet none of these criteria): 1. Parapneumonic Effusions and Empyemas Pleural effusions occur in 40% of patients with an underlying bacterial pneumonia. Most of these effusions should resolve with appropriate antibiotic treatment, but if the fluid characteristics predict a "complicated" parapneumonic effusion, urgent tube drainage is indicated to prevent formation of fibrous peels, which may need surgical decortication. If tube thoracostomy drainage is required, a chest tube is placed until drainage rate has decreased to less than 50 mL/d. Postdrainage imaging must be obtained to confirm complete drainage of fluid and to assess the need for placement of a second tube if the fluid has not been adequately drained (as is often seen if the effusion is loculated). Complete sterilization of the cavity is desirable when treating an empyema with 4 to 6 weeks of antibiotics, as is complete obliteration of the space by lung expansion. Multiloculated empyemas are treated further by administering fibrinolytic agents such as streptokinase or urokinase through the chest tube. Which of the following is the most likely pleural fluid characteristic if thoracentesis is performed? Thoracentesis reveals straw-colored fluid with gram-positive diplococci on Gram stain, pH 6. Schedule a follow-up chest x-ray in 2 weeks to document resolution of the effusion. He is found to have a right-sided pleural effusion, which is tapped and is grossly bloody. Congestive heart failure is commonly associated with bilateral pleural effusions, which are transudative, as a consequence of alteration of Starling forces. The effusions of heart failure are best managed by treating the heart failure, for example, with diuretics, and typically do not require thoracentesis. The most common causes of hemorrhagic pleural effusion are malignancy, pulmonary embolism, and tuberculosis. Pulmonary embolism would be suggested by acute onset of dyspnea and pleuritic chest pain rather than this subacute presentation. Similarly, aortic rupture can produce a hemothorax but would have an acute presentation with pain and hemodynamic compromise. Tube thoracostomy or more aggressive drainage of parapneumonic effusion usually is required with gross pus (empyema), positive Gram stain or culture, glucose less than 60 mg/dL, pH less than 7. The most common cause of pleural effusion is congestive heart failure, which typically gives bilateral symmetric transudative effusions and is best treated with diuresis. The most common causes of bloody pleural effusion (in the absence of trauma) are malignancy, pulmonary embolism with infarction, and tuberculosis. Medical and surgical treatment of parapneumonic effusions: an evidence-based guideline. He works as a computer programmer, exercises regularly at a gym, and does not smoke or use illicit drugs. His father suffered his first heart attack at age 36 years and eventually died of complications of heart disease at age 49 years. Know the risk factors for developing coronary artery disease and know how to estimate the risk for coronary events using the Framingham risk scoring system. Be familiar with the recommendations for cholesterol screening and for the treatment of low-, intermediate-, and high-risk patients. Understand how the different classes of lipid-lowering agents affect lipid levels and the potential side effects of those agents. He does not have any apparent secondary causes of dyslipidemia, and has no signs or symptoms of vascular disease. Because of his very high lipid levels and family history, he is a high-risk patient and, thus, should be counseled about lipid-lowering medical therapy. Because of the association of hypercholesterolemia and development of atherosclerotic heart disease, most authorities recommend routine screening of average-risk individuals at least every 5 years. Management of patients with hypercholesterolemia involves assessment of other atherosclerotic risks to estimate the 10-year risk of coronary events, such as fatal or nonfatal myocardial infarction. Patients with multiple risk factors then are assigned to high risk (>20%), intermediate risk (10%-20%), or low risk (<10%). One should exclude a secondary cause of lipid disorder, either by clinical or laboratory evaluation. The most common underlying causes of dyslipidemia are hypothyroidism and diabetes mellitus. Other conditions to consider are obstructive liver disease, chronic renal failure/nephrotic syndrome, and medication side effects (progestins, anabolic steroids, corticosteroids). Homozygotes for this condition may develop atherosclerotic disease in childhood and usually require intensive lipidlowering drug therapy. These changes include a diet low in saturated fat (<7% of total daily calories) and low in cholesterol (<200 mg/d), as well as exercise, which can help to lower cholesterol. Low-grade myalgias occur in <10% of patients, but severe myopathy is reported in 0. Less commonly, elevated liver enzymes, or even severe hepatitis, have been reported. When these drugs are used, routine clinical or laboratory monitoring for these effects is advisable. He watches his diet, plays tennis, exercises 3 to 5 times per week, and appears to be in good physical condition. The recommended interval for cholesterol screening in this population of healthy adults is every 5 years. He had no headache, no diminishment of consciousness, and no abnormal involuntary movements. The corner of his mouth droops, with slight flattening of the right nasolabial fold, but he is able to fully elevate his eyebrows. His strength is 4/5 in his right arm and hand, and the rest of his neurologic examination is normal. He has no carotid bruits, his heart rhythm is regular with no murmur but with an S4 gallop. He denies headache, diminishment of consciousness, or abnormal involuntary movements. Two weeks ago, he had a transient painless loss of vision in his left eye, which resolved spontaneously within a few hours. Know the most common mechanisms for ischemic stroke: carotid stenosis, cardioembolism, and small-vessel disease. Understand the evaluation of a stroke patient with the goal of secondary prevention. Learn which patients are best managed with medical therapy and which patients benefit from carotid endarterectomy. Considerations Patients who present with acute focal neurologic deficits require rapid evaluation for suspected stroke. He has established atherosclerotic coronary disease but no known carotid artery disease. He denies headache, which is important because migraine headache may be associated with neurologic deficits; it would be rare for an elderly man to have the first presentation of migraine headache. Various neurologic diseases, such as multiple sclerosis, may be characterized by complete resolution of neurologic deficits, but the symptoms usually last longer than 24 hours. His evaluation will be focused on secondary prevention of another, perhaps more devastating cerebrovascular event. With these symptoms, if there is more than 70% stenosis of the left internal carotid artery, the possibility of left carotid endarterectomy should be discussed. The differential diagnosis includes classic migraine, postictal paralysis, seizures, cerebral hemorrhage, or even slow-evolving intracranial processes such as subdural hematoma, abscess, or tumors, which can suddenly produce symptoms because of edema or hemorrhage or result in seizure activity. However, clinical evaluation and imaging studies of the brain should be sufficient to exclude most or all of these diagnoses. The focal neurologic symptoms produced by ischemia depend on the area of the cerebral circulation involved and may include (1) amaurosis fugax, (2) hemiparesis, (3) hemianesthesia, (4) aphasia, or (5) dizziness/vertigo as a result of vertebrobasilar insufficiency. Pertinent historical factors include onset, course, and duration of symptoms, atherosclerotic risk factors, and relevant medical history (ie, atrial fibrillation). In this patient, the first symptom was amaurosis fugax due to cholesterol emboli, called Hollenhorst plaques, which often can be seen lodged in the retinal artery. Auscultation for carotid bruits, cardiac murmurs, assessment of cardiac rhythm, evidence of embolic events to other parts of the body, and a complete neurologic examination should also be assessed. Laboratory data that should always be obtained include a complete blood count, fasting lipid profile, and serum glucose level. Other laboratory data, such as an erythrocyte sedimentation rate in elderly populations to evaluate for temporal arteritis, should be tailored to the patient. Carotid Doppler ultrasound and magnetic resonance angiography are effective noninvasive imaging studies and are often used as first-line diagnostic tools. Stroke prevention begins with antiplatelet therapy, and aspirin should be used in all cases unless there is a contraindication to its use. Use of clopidogrel or combination aspirin and dipyridamole may be slightly superior to aspirin for stroke prevention but at a substantially higher dollar cost. Combination therapy with aspirin and clopidogrel has not been shown to provide greater benefit in stroke prevention but does produce a higher rate of bleeding complications. For patients with cardioembolic stroke as a result of atrial fibrillation, long-term anticoagulation with warfarin (Coumadin) is recommended. The oral direct thrombin inhibitor dabigatran has recently been approved for patients with atrial fibrillation, and is comparable in efficacy to warfarin. For patients with small-vessel disease producing lacunar infarctions, blood pressure control and antiplatelet agents are the mainstays of therapy. Surgical endarterectomy for severe carotid artery stenosis has successfully reduced the long-term risk of stroke in both symptomatic and asymptomatic patients. However, the risk reduction was smaller than in symptomatic patients, from 11% to 5% over 5 years compared to medical management. It should also be noted that the surgery is not without risk and can actually cause strokes. In both trials, the stipulation was made that in order to achieve the risk reduction benefit; surgery should be performed in a center with very low surgical morbidity and mortality. For asymptomatic patients, the benefits of the procedure do not begin to exceed the perioperative morbidity for at least 2 years, so it should be viewed as a "long-term investment" in patients with relatively low comorbidity and a long life expectancy. Carotid angioplasty and stenting is another procedure available for patients with carotid stenosis but, like endarterectomy, also carries a risk of embolization and stroke.
Syndromes
Drop in blood pressure
Have symptoms of shock, such as fainting, excessive sweating, or confusion
Vomiting
Pelvic exam in women
You will usually be asked not to drink or eat anything after midnight the night before the surgery.
Pain or achiness in the abdomen above the pubic bone, in the lower back, in the area between the genitals and anus, or in the testicles
Impotence and gynaecomastia always occur in men impotence quoad hoc 20 mg cialis jelly sale, and withdrawal bleeding may be a problem in women impotence 28 years old buy cheap cialis jelly 20 mg online. Ethinylestradiol is the most potent oestrogen available; unlike other oestrogens it is only slowly metabolised in the liver impotence 60784 generic cialis jelly 20 mg without prescription. Medroxyprogesterone or megestrol are usually chosen and can be given orally; high-dose or parenteral treatment cannot be recommended impotence surgery best 20 mg cialis jelly. Breast cancer impotence at 75 discount 20mg cialis jelly fast delivery, 40 mg daily erectile dysfunction pump australia buy cheap cialis jelly 20mg line, increased to 60 mg daily if required Preparations Section 6 impotence zoloft buy 20 mg cialis jelly free shipping. They do not inhibit ovarian oestrogen synthesis and should not be used in premenopausal women erectile dysfunction foods that help order cialis jelly 20 mg on-line. Anastrozole and letrozole are non-steroidal aromatase inhibitors; exemestane is a steroidal aromatase inhibitor. Aromatase inhibitors are usually prescribed as initial adjuvant therapy in postmenopausal women with oestrogen-receptor-positive tumours; tamoxifen, an oestrogen-receptor antagonist, is used if an aromatase inhibitor is not appropriate. Adjuvant hormone antagonist therapy should generally be continued for 5 years following removal of the tumour. Premenopausal women with oestrogen-receptor-positive breast cancer who decline chemotherapy may benefit from treatment with goserelin (section 8. Aromatase inhibitors, such as anastrozole or letrozole, are the preferred treatment in postmenopausal women with oestrogen-receptor-positive advanced breast cancer, a long disease-free interval following treatment for early breast cancer, and disease limited to bone or soft tissues; tamoxifen can be used if aromatase inhibitors are not suitable. For operable breast cancer, treatment before surgery (neoadjuvant therapy) reduces the size of the tumour and facilitates breast-conserving surgery; hormone antagonist therapy. Tamoxifen should be considered for pre- and perimenopausal women with oestrogen-receptor-positive breast cancer not previously treated with tamoxifen. Ovarian suppression is used in pre- and perimenopausal women who have had disease progression despite treatment with tamoxifen. Cytotoxic chemotherapy is indicated for advanced steroid hormone-receptor-negative tumours and for aggressive disease, particularly when metastases involve visceral sites. Early breast cancer All women should be considered for adjuvant therapy following surgical removal of the tumour. Choice of adjuvant treatment is determined by the risk of recurrence, steroid hormone-receptor status of the primary tumour, and menopausal status. Women with steroid hormone-receptor-positive breast cancer are considered for hormone-antagonist therapy (preceded by cytotoxic chemotherapy if necessary) whilst women with steroid hormone-receptor-negative breast cancer should be considered for cytotoxic chemotherapy. Cytotoxic drugs used in breast cancer An anthracycline combined with fluorouracil (section 8. Cyclophosphamide, methotrexate, and fluorouracil can be useful if an anthracycline is inappropriate. For women who have not previously received chemotherapy, an anthracycline (such as doxorubicin or epirubicin) alone or in combination with another cytotoxic drug is the standard initial therapy for metastatic breast disease. Patients with anthracycline-refractory or resistant disease should be considered for treatment with a taxane (section 8. Other cytotoxic drugs with activity against breast cancer include capecitabine (section 8. Patients should be informed of the risk of endometrial cancer and told to report relevant symptoms promptly Contra-indications treatment of infertility contraindicated if personal or family history of idiopathic venous thromboembolism or genetic predisposition to thromboembolism Pregnancy avoid-possible effects on fetal development; effective contraception must be used during treatment and for 2 months after stopping Breast-feeding suppresses lactation; avoid unless potential benefit outweighs risk Side-effects hot flushes, vaginal bleeding and vaginal discharge (important: see also Endometrial Changes under Cautions), suppression of menstruation in some premenopausal women, pruritus vulvae, gastrointestinal disturbances, headache, light-headedness, tumour flare, decreased platelet counts; occasionally oedema, rarely hypercalcaemia if bony metastases, alopecia, rashes, uterine fibroids; also visual disturbances (including corneal changes, cataracts, retinopathy); leucopenia (sometimes with anaemia and thrombocytopenia), rarely neutropenia; hypertriglyceridaemia reported rarely (sometimes with pancreatitis); thromboembolic events reported (see below); liver enzyme changes (rarely fatty liver, cholestasis, hepatitis); rarely interstitial pneumonitis, hypersensitivity reactions including angioedema, Stevens-Johnson syndrome, bullous pemphigoid; see also notes above Risk of thromboembolism Tamoxifen can increase the risk of thromboembolism particularly during and immediately after major surgery or periods of immobility (consider interrupting treatment to initiate anticoagulant measures). Patients should be made aware of the symptoms of thromboembolism and advised to report sudden breathlessness and any pain in the calf of one leg 8 Malignant disease and immunosuppression Dose. Caution is required in patients with metabolic bone disease because reduced bone mineral density can occur. Side-effects the gonadorelin analogues cause sideeffects similar to the menopause in women and orchidectomy in men and include hot flushes and sweating, sexual dysfunction, vaginal dryness or bleeding, and gynaecomastia or changes in breast size. Signs and symptoms of prostate or breast cancer may worsen initially (managed in prostate cancer with anti-androgens, see above). Other side-effects include hypersensitivity reactions (rashes, pruritus, asthma, and rarely anaphylaxis), injection site reactions (see Cautions), headache (rarely migraine), visual disturbances, dizziness, arthralgia and possibly myalgia, hair loss, peripheral oedema, gastro-intestinal disturbances, weight changes, sleep disorders, and mood changes. By subcutaneous injection, 500 micrograms every 8 hours for 7 days, then intranasally, 1 spray into each nostril 6 times daily (see also notes above) Counselling Avoid use of nasal decongestants before and for at least 30 minutes after treatment. Standard treatments include bilateral subcapsular orchidectomy or use of a gonadorelin analogue (buserelin, goserelin, histrelin, leuprorelin, or triptorelin). No entirely satisfactory therapy exists for disease progression despite this treatment (hormone-refractory prostate cancer), but occasional patients respond to other hormone manipulation. Bone disease can often be palliated with irradiation or, if widespread, with strontium or prednisolone (section 6. Gonadorelin analogues Gonadorelin analogues are as effective as orchidectomy or diethylstilbestrol (section 8. They cause initial stimulation then depression of luteinising hormone release by the pituitary. See under preparations below Zoladex (AstraZeneca) A Implant, goserelin (as acetate) 3. See under preparations below Injection (powder for suspension), triptorelin (as pamoate), net price 22. Cyproterone acetate and flutamide are also licensed for use alone in patients with metastatic prostate cancer refractory to gonadorelin analogue therapy. Bicalutamide is used for prostate cancer either alone or as an adjunct to other therapy, according to the clinical circumstances. Abiraterone (in combination with prednisone or prednisolone) and enzalutamide are licensed for metastatic castration-resistant prostate cancer in patients whose disease has progressed during or after treatment with a docetaxel-containing chemotherapy regimen. Abiraterone is also used to treat metastatic castration-resistant prostate cancer in patients who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. Medical castration with a luteinising hormone-releasing hormone analogue should be continued during treatment with abiraterone in patients not surgically castrated. This guidance does not cover the use of enzalutamide for metastatic hormone-relapsed prostate cancer previously treated with abiraterone. Locally advanced prostate cancer at high risk of disease progression, 150 mg once daily. Locally advanced, non-metastatic prostate cancer when surgical castration or other medical intervention inappropriate, 150 mg once daily. Liver function tests should be performed before and regularly during treatment and whenever symptoms suggestive of hepatotoxicity occur-if confirmed cyproterone should normally be withdrawn unless the hepatotoxicity can be explained by another cause such as metastatic disease (in which case cyproterone should be continued only if the perceived benefit exceeds the risk) Dose. Lanreotide and octreotide are indicated for the relief of symptoms associated with neuroendocrine (particularly carcinoid) tumours and acromegaly. Additionally, lanreotide is licensed for the treatment of thyroid tumours and octreotide is also licensed for the prevention of complications following pancreatic surgery. Octreotide long-acting depot injection is licensed for treatment of advanced neuroendocrine tumours of the midgut, or treatment where primary origin is not known but non-midgut sites of origin have been excluded. Growth hormone-secreting pituitary tumours can expand causing serious complications; during treatment with somatostatin analogues patients should be monitored for signs of tumour expansion. In insulinoma an increase in the depth and duration of hypoglycaemia may occur (observe patients when initiating treatment and changing doses); in diabetes mellitus, insulin or oral antidiabetic requirements may be reduced. Patients with carcinoid tumours must only receive lanreotide after excluding the presence of an obstructive intestinal tumour. Postprandial glucose tolerance may be impaired and rarely persistent hyperglycaemia occurs with chronic administration; hypoglycaemia has also been reported. Gallstones have been reported after long-term treatment (abrupt withdrawal of subcutaneous octreotide is associated with biliary colic and pancreatitis). Iron salts may be harmful and result in iron overload if given alone to patients with anaemias other than those due to iron deficiency. Before starting treatment, it is important to exclude any serious underlying cause of the anaemia. Prophylaxis with an iron preparation may be appropriate in malabsorption, menorrhagia, pregnancy, after subtotal or total gastrectomy, in haemodialysis patients, and in the management of low birth-weight infants such as preterm neonates. The oral dose of elemental iron for iron-deficiency anaemia should be 100 to 200 mg daily. It is customary to give this as dried ferrous sulfate, 200 mg (: 65 mg elemental iron) three times daily; for prophylaxis of irondeficiency anaemia, a dose of ferrous sulfate 200 mg once or twice daily may be effective. There is no justification for the inclusion of other ingredients, such as the B group of vitamins (except folic acid for pregnant women, see notes above and on p. Modified-release preparations Modified-release preparations of iron are licensed for once-daily dosage, but have no therapeutic advantage and should not be used. These preparations are formulated to release iron gradually; the low incidence of side-effects may reflect the small amounts of iron available for absorption as the iron is carried past the first part of the duodenum into an area of the gut where absorption may be poor. When the haemoglobin is in the reference range, treatment should be continued for a further 3 months to replenish the iron stores. Nausea and epigastric pain are doserelated, but the relationship between dose and altered bowel habit (constipation or diarrhoea) is less clear. Oral iron, particularly modified-release preparations, can exacerbate diarrhoea in patients with inflammatory bowel disease; care is also needed in patients with intestinal strictures and diverticular disease. Iron preparations taken orally can be constipating, particularly in older patients and occasionally lead to faecal impaction. If side-effects occur, the dose may be reduced; alternatively, another iron salt may be used, but an improvement in tolerance may simply be a result of a lower content of elemental iron. The incidence of side-effects due to ferrous sulfate is no greater than with other iron salts when compared on the basis of equivalent amounts of elemental iron. It is important to note that the small doses of folic acid contained in these preparations are inadequate for the treatment of megaloblastic anaemias. See under preparation below and notes above 9 Nutrition and blood Syrup, ferrous fumarate approx. Parenteral iron is generally reserved for use when oral therapy is unsuccessful because the patient cannot tolerate oral iron, or does not take it reliably, or if there is continuing blood loss, or in malabsorption. Many patients with chronic renal failure who are receiving haemodialysis (and some who are receiving peritoneal dialysis) also require iron by the intravenous route 1. With the exception of patients with severe renal failure receiving haemodialysis, parenteral iron does not produce a faster haemoglobin response than oral iron provided that the oral iron preparation is taken reliably and is absorbed adequately. In the event of a hypersensitivity reaction, treatment should be stopped immediately and appropriate management initiated. The risk of hypersensitivity is increased in patients with known allergies, immune or inflammatory conditions, or those with a history of severe asthma, eczema, or other atopic allergy; in these patients, intravenous iron should only be used if the benefits outweigh the risks. In emergencies, when delay might be dangerous, it is sometimes necessary to administer both substances after the bone marrow test while plasma assay results are awaited. Normally, however, appropriate treatment should not be instituted until the results of tests are available. Vitamin B12 should be given prophylactically after total gastrectomy or total ileal resection (or after partial gastrectomy if a vitamin B12 absorption test shows vitamin B12 malabsorption). There is little place for the use of low-dose vitamin B12 orally and none for vitamin B12 intrinsic factor complexes given by mouth. Hydroxocobalamin has completely replaced cyanocobalamin as the form of vitamin B12 of choice for therapy; it is retained in the body longer than cyanocobalamin and thus for maintenance therapy can be given at intervals of up to 3 months. Folic acid has few indications for long-term therapy since most causes of folate deficiency are self-limiting or will yield to a short course of treatment. It should not be used in undiagnosed megaloblastic anaemia unless vitamin B12 is administered concurrently otherwise neuropathy may be precipitated (see above). For prophylaxis in chronic haemolytic states, malabsorption, or in renal dialysis, folic acid is given daily or sometimes weekly, depending on the diet and the rate of haemolysis. Folinic acid is also effective in the treatment of folatedeficient megaloblastic anaemia but it is generally used in association with cytotoxic drugs (see section 8. Women in the high-risk group who wish to become pregnant (or who are at risk of becoming pregnant) should be advised to take folic acid 5 mg daily and continue until week 12 of pregnancy (women with sickle-cell disease should continue taking their normal dose of folic acid 5 mg daily (or to increase the dose to 5 mg daily) and continue this throughout pregnancy). The risk of a neural tube defect occurring in a child should be assessed and folic acid given as follows: Women at a low risk of conceiving a child with a neural tube defect should be advised to take folic acid as a medicinal or food supplement at a dose of 400 micrograms daily before conception and until week 12 of pregnancy. Women who have not been taking folic acid and who suspect they are pregnant should start at once and continue until week 12 of pregnancy. Couples are at a high risk of conceiving a child with a neural tube defect if either partner has a neural tube defect (or either partner has a family history of neural tube defects), if they have had a previous pregnancy affected by a neural tube defect, or if the woman has coeliac disease (or other malabsorption state), diabetes mellitus, sickle-cell anaemia, or is taking antiepileptic medicines (see also section 4. Prevention of methotrexate-induced side-effects in severe psoriasis [unlicensed], by mouth, see section 13. However, certain forms of sideroblastic anaemia respond to pharmacological doses, possibly reflecting its role as a co-enzyme during haemoglobin synthesis. Pyridoxine is indicated in both idiopathic acquired and hereditary sideroblastic anaemias. Although complete cures have not been reported, some increase in haemoglobin can occur; the dose required is usually high, up to 400 mg daily. Reversible sideroblastic anaemias respond to treatment of the underlying cause but in pregnancy, haemolytic anaemias, and alcohol dependence, or during isoniazid treatment, pyridoxine is also indicated. They include conditions with an immune basis such as autoimmune haemolytic anaemia, immune thrombocytopenias and neutropenias, and major transfusion reactions. Epoetin beta is also used for the prevention of anaemia in preterm neonates of low birth-weight; only unpreserved formulations should be used in neonates because other preparations may contain benzyl alcohol (see Excipients, p. Darbepoetin is a hyperglycosylated derivative of epoetin; it has a longer half-life and can be administered less frequently than epoetin. Methoxy polyethylene glycol-epoetin beta is a continuous erythropoietin receptor activator that is licensed for the treatment of symptomatic anaemia associated with chronic kidney disease. Other factors, such as iron or folate deficiency, that contribute to the anaemia of chronic renal failure should be corrected before treatment and monitored during therapy. Aluminium toxicity, concurrent infection, or other inflammatory disease can impair the response to erythropoietin. If different erythropoiesis-stimulating agents are equally suitable, the product with the lowest acquisition cost for the course of treatment should be used. Reduce dose by approximately 25% if rise in haemoglobin concentration exceeds 2 g/100 mL over 4 weeks or if haemoglobin concentration exceeds 12 g/100 mL; if haemoglobin concentration continues to rise, despite dose reduction, suspend treatment until haemoglobin concentration decreases and then restart at a dose approximately 25% lower than the previous dose. When changing route give same dose then adjust according to weekly or fortnightly haemoglobin measurements. Pure red cell aplasia There have been very rare reports of pure red cell aplasia in patients treated with erythropoietins. In patients who develop a lack of efficacy with erythropoietin therapy and with a diagnosis of pure red cell aplasia, treatment with erythropoietins must be discontinued and testing for erythropoietin antibodies considered. Patients who develop pure red cell aplasia should not be switched to another form of erythropoietin. Discontinue approximately 4 weeks after ending chemotherapy 9 Nutrition and blood Aranesp (Amgen) A Injection, prefilled syringe, darbepoetin alfa, 25 micrograms/mL, net price 0. Reduce dose by approximately 25% if rise in haemoglobin concentration exceeds 2 g/100 mL over 4 weeks or if haemoglobin concentration approaches or exceeds 12 g/100 mL; if haemoglobin concentration continues to rise, despite dose reduction, suspend treatment until haemoglobin concentration decreases and then restart at a dose approximately 25% lower than the previous dose Prevention of anaemia of prematurity in neonates with birth-weight of 0.
