Importance and management the interaction between senna and corticosteroids is theoretical infection hole in skin 500 mg azithromycin overnight delivery, but be aware of the potential in patients who regularly use antibiotic resistance malaysia order 100mg azithromycin mastercard, or abuse antibiotic keflex breastfeeding cheap azithromycin 500mg fast delivery, anthraquinone-containing substances such as senna virus - ruchki zippy generic 500 mg azithromycin. However infection pus generic azithromycin 100mg free shipping, note that antibiotics for dogs online generic azithromycin 250 mg without a prescription, if anthraquinone laxatives are used as recommended (at a dose producing a comfortable soft-formed motion), then this interaction would not be expected to be clinically relevant. An overview of herbal supplement utilization with particular emphasis on possible interactions with dental drugs and oral manifestations. Senna + Diuretics; Potassium-depleting Theoretically, patients taking potassium-depleting diuretics could experience excessive potassium loss if they also regularly use, or abuse, anthraquinone-containing substances such as senna. Clinical evidence For information on the additive risk of hypokalaemia with the use of potassium-depleting diuretics and abuse of anthraquinone-containing laxatives. Experimental evidence the effects of the anthraquinones found in senna (rhein, danthron, sennidins A and B, sennosides A and B), and senna leaf infusion (senna tea), on the absorption of furosemide 100 micromoles, a poorly permeable drug, was examined in human cell lines. Furosemide permeability was reduced by more than a third by the sennidins and sennosides, but senna leaf infusion had little effect. The changes in furosemide absorptive permeability may be caused by interference with P-glycoprotein or other transporter proteins. The authors suggest that an effect of anthraquinonecontaining laxatives on the absorption of poorly permeable drugs such as furosemide cannot be excluded. S Senna + Digitalis glycosides Theoretically, digitalis toxicity could develop if patients regularly use, or abuse, anthraquinone-containing substances such as senna. Clinical evidence For the risk of digitalis toxicity including cardiac arrhythmias because of hypokalaemia induced by abuse of anthraquinone laxatives, see Aloes + Digitalis glycosides, page 28. For mention of a case of digoxin toxicity and mild hypokalaemia in a patient taking digoxin and furosemide, who started to take a laxative containing rhubarb and liquorice, see Liquorice + Digitalis glyosides, page 274. Experimental evidence the effects of anthraquinones found in senna (rhein 100 micromoles, danthron 100 micromoles, sennidins A and B, sennosides A and B), and senna leaf infusion (senna tea) 10 mg/mL, on the absorption of digoxin was examined in human cell lines. Senna + Estradiol Senna does not appear to affect the pharmacokinetics of estradiol. Clinical evidence In a clinical study in 19 women, the maximum daily tolerated dose of senna tablets (Senokot) was taken for 10 to 12 days with a single 1. Mechanism It was thought that reducing intestinal transit time with senna might lead to reduced blood levels of estradiol. Importance and management Limited evidence suggests that there is unlikely to be a clinically relevant pharmacokinetic interaction between anthraquinone-containing laxatives and estradiol. Experimental evidence the effects of the anthraquinones found in senna (rhein, danthron, sennidins A and B, sennosides A and B), and senna leaf infusion (senna tea), on the absorption of paracetamol 100 micromoles was examined in human cell lines. Importance and management Evidence is sparse, but what is known suggests that the use of anthraquinone-containing laxatives is unlikely to affect the intestinal permeability of paracetamol (acetaminophen). Senna + Herbal medicines; Liquorice Consider Liquorice + Laxatives, page 275, for the potential additive effects of anthraquinone-containing laxatives and liquorice. Senna + Propranolol the information regarding the use of senna with propranolol is based on experimental evidence only. S Senna + Ketoprofen the interaction between senna and ketoprofen is based on experimental evidence only. Experimental evidence the effects of the anthraquinones found in senna (rhein, danthron, sennidins A and B, sennosides A and B), and senna leaf infusion (senna tea), on the absorption of ketoprofen 100 micromoles was examined in human cell lines. The enhanced permeability caused by senna leaf infusion is more difficult to explain because of the many different active compounds contained within the extract. Anthranoid laxatives influence the absorption of poorly permeable drugs in human intestinal cell culture model (Caco-2). Experimental evidence the effects of the anthraquinones found in senna (rhein, danthron, sennidins A and B, sennosides A and B), and senna leaf infusion (senna tea), on the absorption of propranolol 100 micromoles, was examined in human cell lines. Importance and management Evidence is sparse, but what is known suggests that the use of anthraquinone-containing laxatives seems unlikely to affect the intestinal permeability of propranolol. Senna + Quinidine Quinidine plasma levels can be reduced by the anthraquinonecontaining laxative senna. Clinical evidence In a study in 7 patients with cardiac arrhythmias taking sustainedrelease quinidine bisulfate 500 mg every 12 hours, senna reduced plasma quinidine levels, measured 12 hours after the last dose of quinidine, by about 25%. Senna + Paracetamol (Acetaminophen) the information regarding the use of senna with paracetamol is based on experimental evidence only. Importance and management the modest reduction in quinidine levels might be of clinical importance in patients whose plasma levels are barely adequate to control their arrhythmia. Senna + Verapamil the information regarding the use of senna with verapamil is based on experimental evidence only. Importance and management Evidence is sparse, but what is known suggests that the use of anthraquinone-containing laxatives seems unlikely to affect the intestinal permeability of verapamil. Not to be confused with asparagus, page 44, which is Asparagus officinalis, the species used as a food. Constituents the root and rhizome of shatavari contain a series of steroidal saponins, the shatavarins and others, based on sarsapogenin, diosgenin and arasapogenin. The polycyclic alkaloid asparagamine A, benzofurans such as racemofuran and racemosol, and the isoflavone 8-methoxy-5,6,4"-trihydroxyisoflavone 7-O-D-glucopyranoside are also present. It is also reported to be antispasmodic, aphrodisiac, demulcent, diuretic, anti-diarrhoeal, antirheumatic and antidiabetic. Some of these indications are supported by pharmacological (but little clinical) evidence. Interactions overview Shatavari may have additive effects with conventional antidiabetic drugs, and may alter the absorption of a number of drugs by delaying gastric emptying. Shatavari contains phytoestrogens and therefore has the potential to be antagonistic or synergistic with oestrogens or oestrogen antagonists. Evidence, mechanism, importance and management In a crossover study in 8 healthy subjects,1 powdered root of shatavari 2 g reduced the gastric emptying half-life from a mean baseline of about 160 minutes to 101 minutes after two radio-labelled jam sandwiches were eaten. This was similar to the effect of a single 10-mg dose of oral metoclopramide (85 minutes). If shatavari increases the gastric emptying rate, it has the potential to increase or decrease the absorption of other drugs that are taken concurrently. Metoclopramide is known to have this effect and modestly decreases the absorption of atovaquone, digoxin and ketoprofen, and increases the absorption of ciclosporin, dantrolene, morphine and paracetamol (acetaminophen). Based on the limited evidence presented, it is possible that shatavari might interact similarly. Until more is known, some caution might be appropriate; however, note that, with the exception of atovaquone, in most cases the interactions of metoclopramide with these drugs are of limited clinical importance. Effect of Asparagus racemosus (Shatavari) on gastric emptying time in normal healthy volunteers. Shatavari + Antidiabetics the interaction between shatavari and antidiabetics is based on experimental evidence only. Evidence, mechanism, importance and management In pharmacological studies, shatavari extracts have been shown to lower blood-glucose and stimulate insulin secretion. In one in vitro study, the insulin stimulatory effect of various extracts and partition fractions of shatavari was potentiated by tolbutamide. The evidence is too slim to say whether a clinically important effect is likely for usual preparations of the herb, but an additive antidiabetic effect with conventional medicines for diabetes seems possible. Bear this information in mind in the event of an unexpected response to treatment. Insulin secretory actions of extracts of Asparagus racemosus root in perfused pancreas, isolated islets and clonal pancreatic -cells. Shatavari + Oestrogens or Oestrogen antagonists the interaction between shatavari and oestrogens or oestrogen antagonists is based on a prediction only. Shatavari + Miscellaneous Limited evidence suggests that shatavari increases the gastric emptying rate similarly to metoclopramide, which is known to decrease the absorption of atovaquone, digoxin and ketoprofen, and increase the absorption of ciclosporin, dantrolene, morphine Evidence, mechanism, importance and management Shatavari contains phytoestrogens and has been investigated in a variety of pharmacological and clinical studies for its effect on lactation, dysfunctional uterine bleeding, premenstrual syndrome and menopausal symptoms; this has been the subject of a review. Previous reports about its possible toxicity have been found to be because of contamination with Teucrium species; skullcap itself is now considered to be safe to use. Constituents the major active components of skullcap are the flavonoids scutellarin, scutellarein, baicalein, baicalin (the glucuronide of baicalein), dihydrobaicalin, apigenin, luteolin and other methoxyflavones. Pharmacokinetics No relevant pharmacokinetic data found for skullcap, but see flavonoids, page 186, for information on individual flavonoids present in the herb. Interactions overview No interactions with skullcap found, but for information on the interactions of individual flavonoids present in skullcap, see under flavonoids, page 186. Use and indications Skullcap has been used traditionally as a sedative and to treat S 355 Soya Glycine max (L. This highlights the problems of extrapolating the findings of in vitro studies to clinical situations. The pharmacokinetics of the isoflavone constituents of soya are further discussed under isoflavones, page 258. Constituents the isoflavones in soya beans consist mainly of genistein and daidzein, with smaller amounts of isoformononetin, ononin, glycetein, desmethyltexasin and others. They are present mainly as glycosides, and the amount varies between the different soya products. S Interactions overview Soya products may increase the metabolism of caffeine and reduce the absorption of levothyroxine. Potential interactions of isoflavone constituents of soya are covered under isoflavones; see antibacterials, page 260, nicotine, page 261, paclitaxel, page 261, tamoxifen, page 262, and theophylline, page 263. Clinical review: a critical evaluation of the role of soy protein and isoflavone supplementation in the control of plasma cholesterol concentrations. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. Cassidy A, Albertazzi P, Lise Nielsen I, Hall W, Williamson G, Tetens I, Atkins S, Cross H, Manios Y, Wolk A, Steiner C, Branca F. Critical review of health effects of soyabean phyto-oestrogens in post-menopausal women. Soy protein, isoflavones, and cardiovascular health: an American Heart Association Science Advisory for professionals from the Nutrition Committee. Use and indications Soya is a widely used food, particularly in Japanese and Chinese cuisine. Fermented products include soy sauce, natto and miso, and these can contain high concentrations of the isoflavones. There are numerous purported benefits of soya protein, the most well studied being possible reductions in hyperlipidaemia, menopausal symptoms and osteoporosis, and prevention of some cancers. Epidemiological studies suggest that a diet with a high intake of soya might protect against breast cancer. One paper notes that many of the demonstrable actions of isoflavones in soya are attributed to the aglycones genistein and daidzein; however, these occur in negligible amounts unless the product has been fermented. Despite numerous studies and meta-analyses, the health benefits of soya have not been conclusively proven and remain controversial. For the theoretical possibility that broadspectrum antibacterials might reduce the metabolism of the isoflavone constituents of soya, such as daidzein, by colonic bacteria, and so alter their efficacy, see Isoflavones + Antibacterials, page 260. Soya + Levothyroxine and related drugs Soya + Caffeine Soya products may increase the metabolism of caffeine. Clinical evidence Caffeine elimination is low in neonates, but increases faster in those receiving formula feeds (type not specified), than in breast-fed infants. Mechanism Neonates are less able to metabolise caffeine than adults: hepatic metabolism matures in the first year of life. Importance and management Clinical evidence in support of an interaction between soya and caffeine is limited, because the two studies do not state the formula feeds used, although it seems likely that soya feeds are implicated; this suggestion is supported by experimental evidence. In infants, caffeine is dosed individually, but be aware that required doses are likely to increase in those receiving formula feeds, including soyabased formula. Effect of diet on the development of drug metabolism by cytochrome P-450 enzymes in healthy infants. Induction of cytochrome P450 1A by cow milk-based formula: a comparative study between human milk and formula. Soya products or soya isoflavones might increase the dose required of thyroid hormone replacement therapy. Taking the soya protein cocktail in the morning and the levothyroxine in the evening avoided this effect. However, soya isoflavones do not appear to cause thyroid hormone abnormalities in euthyroid individuals (also reviewed6). Mechanism Soya isoflavones clearly inhibit thyroid peroxidase; however, hypothyroidism does not usually occur unless iodine deficiency is also present. Soya formula or other similar products might decrease levothyroxine absorption in some individuals. Importance and management There is a good body of evidence, which suggests that soya products or soya isoflavones might increase the dose required of thyroid hormone replacement therapy. It would seem prudent to closely monitor the resolution of primary hypothyroidism in infants receiving soya formula, and expect to use higher dose of levothyroxine than anticipated in these individuals. Monitor thyroxine levels, and either discontinue the soya formula or further increase the dose if necessary. Similar precautions would seem prudent if patients receiving levothyroxine wish to take soya supplements; however, remember that the intake of soya supplementation will need to remain relatively constant. Use of soy protein supplement and resultant need for increased dose of levothyroxine. Persistent hypothyroidism in an infant receiving a soy formula: case report and review of the literature. Abnormal thyroid function tests in infants with congenital hypothyroidism: the influence of soy-based formula. However, other soya products such as dried textured soya protein and fresh soya beans are unlikely to contain important amounts of tyramine. Successful treatment of a monoamine oxidase inhibitor-tyramine hypertensive emergency with intravenous labetolol [sic]. Tyramine content of preserved and fermented foods or condiments of Far Eastern cuisine. Effects of soy protein and soybean isoflavones on thyroid function in healthy adults and hypothyroid patients: a review of the relevant literature.
Uroporphyrin accumulation produced by halogenated biphenyls in chick-embryo hepatocytes infection 3 weeks after wisdom teeth removal discount azithromycin 500mg line. Chemical contaminants in wildlife from the Mohawk nation at Akwesasne and the vicinity of the General Motors Corporation/Central Foundry Division Massena virus d68 symptoms buy cheap azithromycin 500mg, New York plant antibiotic 3 pills purchase azithromycin 250mg on-line. Lawrence river drainage on lands of the Mohawk nation at Akwesasne treatment for sinus infection over the counter generic azithromycin 500mg online, and near the General Motors Corporation central foundry division Massena antibiotics yeast infection yogurt azithromycin 500 mg low cost, New York Plant antibiotic treatment for cellulitis discount azithromycin 100mg without a prescription. Metabolic and health consequences of occupational exposure to polychlorinated biphenyls. Transport of incinerated organochlorine compounds to air, water, microlayer, and organisms. Effect of Aroclor 1248 concentration on the rate and extent of polychlorinated biphenyl dechlorination. Effects of chlorobenzoate transformation on the pseudomonas-testosteroni biphenyl and chlorobiphenyl degradation pathway. Toxicokinetic and toxicodynamic influences on endocrine disruption by polychlorinated biphenyls. An assessment of the reproductive toxic potential of Aroclor 1254 in female Sprague-Dawley rats. Human exposure to polychlorinated biphenyls at toxic waste sites: Investigations in the United States. A pilot study of serum polychlorinated biphenyl levels in persons at high risk of exposure in residential and occupational environments. Evaluation of potential health effects associated with serum polychlorinated biphenyl levels. Relative abundance of organochlorine pesticides and polychlorinated biphenyls in adipose tissue and serum of women in Long Island, New York. Concentrations and spatial variations of cyclodienes and other organochlorines in herring and perch from the Baltic Sea. Adsorption and reduction in bioactivity of polychlorinated biphenyl (Aroclor 1254) to redroot pigweed by soil organic matter and montmorillonite clay. Translocation of polychlorobiphenyls in soil into plants: A study by a method of culture of soybean sprouts. Parameters of immunological competence in subjects with high consumption of fish contaminated with persistent organochlorine compounds. Mortality and cancer incidence among Swedish fishermen with a high dietary intake of persistent organochlorine compounds. Fish consumption and exposure to persistent organochlorine compounds, mercury, selenium and methylamines among Swedish fishermen. Estimation of the atmospheric and nonatmospheric contributions and losses of polychlorinated biphenyls for Lake Michigan on the basis of sediment records of remote lakes. Selection of enhanced polychlorinated biphenyl-degrading bacterial strains for bioremediation: Consideration of branching pathways. Combined effects of polychlorinated biphenyls and methylmercury on hepatic microsomal monooxygenases and the hepatic action of bromobenzene. Transfer and distribution of accumulated (14C)polychlorinated biphenyls from maternal to fetal and suckling rats. Contamination and specific accumulation of organochlorine and butyltin compounds in deep-sea organisms collected from Suruga Bay, Japan. Enhancement of fecal excretion of polychlorinated biphenyls by the addition of rice bran fiber to the diet. The effect of inorganic lead and/or a polychlorinated biphenyl on the developing immune system of mice. The effect of lead and polychlorinated biphenyl exposure on rat natural killer cell cytotoxicity. Absorption efficiency and biological half-life of individual chlorobiphenyls in rats treated with Kanechlor products. Enhancing effect of inducers of liver microsomal enzymes on induction of hyperplastic liver nodules by N-2-fluorenylacetamide in rats. The relation of occupational polychlorinated biphenyl exposure to cancer and total mortality. The relation of polychlorinated biphenyls to birth weight and gestational age in the offspring of occupationally exposed mothers. Effect of polychlorinated biphenyls on the immune responses of Rhesus monkeys and mice. Sources and fate of polychlorinated dibenzodioxins, dibenzofurans and related compounds in human environments. Chlorodibenzodioxins, chlorodibenzofurans and related compounds in the effluents from combustion processes. Health advisories for consumers of Great Lakes sport fish: Is the message being received? Neurochemical effects of polychlorinated biphenyls: an overview and identification of research needs. The effects of polychlorinated biphenyls given prenatally on the neurobehavioral development of mice. Polychlorinated biphenyls and the developing nervous system cross-species comparisons. Bench-scale testing of selected remediation alternatives for contaminated sediments. Aroclor 1242 stimulates the production of inositol phosphates in polymorphonuclear neutrophils. Phospholipase A2 is involved in the mechanism of activation of neutrophils by polychlorinated biphenyls. Polychlorinated biphenyl toxicity in the pregnant Cynomolgus monkey: A pilot study. Immunotoxicity of polychlorinated biphenyls: Present status and future considerations. Effects of Great Lakes fish consumption on the immune system of Sprague-Dawley rats investigated during a two-generation reproductive study: I. Comparative aspects of Aroclor 1254 toxicity in adult Cynomolgus and Rhesus monkeys: A pilot study. Use of a physiological compartmental model for the rat to describe the pharmacokinetics of several chlorinated biphenyls in the mouse. Photolytic transformation of polychlorinated dioxins and dibenzofurans in fly ash. Organochlorine compounds in human breast fat from deceased with and without breast cancer and in a biopsy material from newly diagnosed patients undergoing breast surgery. Reductive ortho and meta-dechlorination of a polychlorinated biphenyl congener by anaerobic microorganisms. Similar rates of decrease of persistent, hydrophobic and particle-reactive contaminants in riverine systems. Chemical contaminants in gray whales (eschrichtius robutus) stranded along the west coast of North America. Estimating bioconcentration potential from octanol/water partition coefficients: In: Mackay D, et al. The New York angler cohort study: Exposure characterization and reproductive and developmental health. Concentrations of dissolved and particulate polychlorinated biphenyls in water from the Saginaw River, Michigan. The fetotoxicity of a polychlorinated biphenyl mixture (Aroclor 1254) in the rabbit and in the rat. Interactions of environmental chemicals with the estrogen and progesterone receptors from the oviduct of the American alligator. Exposure to polychlorinated biphenyls in residential indoor air and outdoor air near a Superfund site. Dermal toxicity studies of technical polychlorinated biphenyls and fractions thereof in rabbits. Immunosuppressive activity of a polychlorinated biphenyl preparation on the humoral immune response in guinea pigs. Quantitative alterations in the liver and adrenal gland in pregnant rats induced by Pyralene 3000. Sampling and analysis artifacts caused by elevated indoor air polychlorinated biphenyl concentrations. Using three-dimensional quantitative structure-activity relationships to examine estrogen receptor binding affinities of polychlorinated hydroxybiphenyls. Great Lakes fish as a source of maternal and fetal exposure to chlorinated hydrocarbons. Global fractionation and cold condensation of low volatility organochlorine compounds in polar regions. The effects of snow and ice on the environmental behaviour of hydrophobic organic chemicals. The importance of snow scavenging of polychlorinated biphenyl and polycyclic aromatic hydrocarbon vapors. Proliferative lesions of the glandular stomach and liver in F344 rats fed diets containing Aroclor 1254. Function of adrenal gland-zona fasciculata in rats receiving polychlorinated biphenyls. Organochlorine compounds in neoplastic and adjacent apparently normal breast tissue. Immunological effects of background exposure to polychlorinated biphenyls and dioxins in Dutch toddlers. Immunologic effects of background prenatal and postnatal exposure to dioxins and polychlorinated biphenyls in Dutch infants. Polychlorinated naphthalenes and other organochlorine contaminants in human adipose and liver tissue. Determination of chlorobiphenyls, with the separation of non-ortho, mono-ortho and di-ortho chloro congeners in fish and sea mammals. Effects of acute or chronic polychlorinated biphenyl ingestion on maternal metabolic homeostasis and on the manifestations of embryotoxicity caused by cyclophosphamide in mice. Extraction and gas chromatography/electron capture analysis of polychlorinated biphenyls in railcar paint scrapings. Accumulation of metals, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons in sediments from the lower Passaic River, New Jersey. Glomerular filtration rate, effective renal blood flow, and maximal tubular excretory capacity in infancy. Microbial reductive dechlorination of trichlorobiphenyls in anaerobic sediment slurries. Low-temperature microbial aerobic degradation of polychlorinated biphenyls in sediment. Influence of ortho-substitution homolog group on polychlorinated bioaccumulation factors and fugacity ratios in plankton and zebra mussels (dreissena polymorpha). Workshop: Effects of endocrine disruptors in the environment on neuronal development and behaviourcurrent knowledge, assessment, gaps. Assay of polychlorinated biphenyl bioaccumulation from sediments by marine benthic copepods using a novel microextraction technique. Subsistence economies in Alaska: Productivity, geography, and development impacts. Environmental organochlorine exposure as a potential etiologic factor in breast cancer. Body burden of polychlorinated biphenyls among persons employed in capacitor manufacturing. Disposition of polychlorinated biphenyl congeners in occupationally exposed persons. Ortho-substituted polychlorinated biphenyls alter calcium regulation by a ryanodine receptor-medicated mechanism: Structural specificity toward skeletal- and cardiac-type microsomal calcium release channels. Ortho-Substituted polychlorinated biphenyls alter microsomal calcium transport by direct interaction with ryanodine receptors of mammalian brain. Toxins and tradition: the impact of food-chain contamination on the Inuit of northern Quebec. The effects of polychlorinated biphenyls and methylmercury, singly and in combination, on mink. The effects of polychlorinated biphenyls and methylmercury, singly and in combination on mink. Influence of incubation temperature on the microbial reductive dechlorination of 2,3,4,6-tetrachlorobiphenyl in two freshwater sediments. Temperature determines the pattern of anaerobic microbial dechlorination of Aroclor 1260 primed by 2,3,4,6-tetrachlorobiphenyl in Woods Pond sediment. Microbial reductive dechlorination of Aroclor 1260 in anaerobic slurries of estuarine sediments. In vitro metabolism of 4-chlorobiphenyl by control and induced rat liver microsomes. Investigation concerning babies born from women who consumed oil contaminated with chlorobiphenyl. Anaerobic dechlorination of polychlorobiphenyls (Aroclor 1242) by pasteurized and ethanol-treated microorganisms from sediments. Analyses of tissues of eight marine species from Atlantic and Pacific coasts for dioxin-like chlorobiphenyls (Cbs) and total Cbs.
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Fluvoxamine strongly inhibits melatonin metabolism in a patient with low-amplitude melatonin profile antibiotics for uti amoxicillin dosage buy 500 mg azithromycin with mastercard. The finding of this study suggests that melatonin might not be as effective in smokers antibiotics for sinus infection and sore throat purchase azithromycin 250mg overnight delivery. Be aware of this possibility virus games online discount 250mg azithromycin, and consider trying an increased melatonin dose if it is not effective in a smoker infection symptoms purchase azithromycin 500mg with mastercard. Importance and management these appear to be the only reports in the literature of a possible interaction between melatonin and warfarin antibiotics homemade azithromycin 250 mg amex. They are difficult to interpret antimicrobial jeans buy generic azithromycin 250mg, since they include both increased and decreased warfarin effects, and it is possible that they are just idiosyncratic cases. Because of these cases, a study designed to exclude a pharmacokinetic/pharmacodynamic interaction would be useful. Until more is known, bear these cases in mind in the event of an unexpected change in coagulation status in patients also taking melatonin supplements. Involvement of cytochrome P-450 isozymes in melatonin metabolism and clinical implications. Evidence, mechanism, importance and management In a single-dose controlled study, there was no pharmacokinetic interaction between thioridazine 50 mg and melatonin 2 mg. Use and indications Melilot is used mainly to treat inflammation, oedema and capillary fragility. For information on the pharmacokinetics of individual flavonoids present in melilot, see under flavonoids, page 186. Constituents the main active constituents of melilot are natural coumarin and its derivatives, melilotin, melilotol, dihydrocoumarin, umbelliferone and scopoletin, which are formed on drying from the glycoside melilotoside. If spoilage and subsequent fermentation occur, some coumarin derivatives can be transformed into the potent anticoagulant dicoumarol (bishydroxycoumarin). Other constituents present are flavonoids (including quercetin) and a number of saponins. For information on the interactions of individual flavonoids present in melilot, see under flavonoids, page 186. She strongly denied taking any anticoagulant drugs, but it was eventually discovered that she had been drinking large quantities of a herbal tea containing among other ingredients tonka beans, melilot and sweet woodruff, all of which might contain natural coumarins. Melilot is known to contain natural coumarins, although these do not possess the minimum structural requirements required for anticoagulant activity. It seems that fermentation and spoilage of the melilot by mould are necessary for anticoagulant effects to occur. Importance and management Evidence appears to be limited to these isolated cases, which are not established. It may be better to advise patients to discuss the use of any herbal products that they wish to try, and to increase monitoring if this is thought advisable. Chiffoleau A, Huguenin H, Veyrac G, Argaiz V, Dupe D, Kayser M, Bourin M, Jolliet P. Constituents the mature fruit (seed) of milk thistle contains silymarin, which is a mixture of the flavonolignans silibinin (silybin), silicristin (silychristin), silidianin (silydianin), isosilibinin and others. Milk thistle fruit also contains various other flavonoids, page 186, such as quercetin, and various sterols. Note that milk thistle leaves do not contain silymarin, and contain the flavonoids, page 186, apigenin and luteolin, and the triterpene, beta-sitosterol. Use and indications Milk thistle is reported to have hepatoprotective properties and is mainly used for liver diseases and jaundice. Traditionally milk thistle was used by nursing mothers for stimulating milk production, as a bitter tonic, demulcent, as an antidepressant and for dyspeptic complaints. Both the fruit and leaves are used as a herbal medicine, but currently the fruit is the main target of investigation because it contains the pharmacologically active silymarin component. A water-soluble salt of the individual flavonolignan silibinin is used intravenously for preventing hepatotoxicity after poisoning with the death cap mushroom Amanita phalloides. It has been suggested that, while in vitro levels of silymarin may cause moderate inhibition of several cytochrome P450 isoenzymes, in vivo levels do not reach inhibitory concentrations and so milk thistle would not be expected to exhibit inhibition at pharmacologically effective concentrations. However, there is no evidence from human pharmacokinetic studies that milk thistle has a clinically important effect on the levels of drugs that are P-glycoprotein substrates, see digoxin, page 294. Interactions overview In vitro studies have suggested that milk thistle may interact with a number of drugs by inhibiting their metabolism by various cytochrome P450 isoenzymes or affecting their transport by P-glycoprotein. However, in vivo studies suggest that any such inhibition is unlikely to be clinically relevant. For information on the interactions of individual flavonoids present in milk thistle, see under flavonoids, page 186. Pharmacokinetics Several studies have investigated the effect of milk thistle extracts on cytochrome P450 isoenzymes and drug transporters. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases. Inhibitory effects of silibinin on cytochrome P-450 enzymes in human liver microsomes. Molecular characterization and inhibition of amanitin uptake into human hepatocytes. M 294 Milk thistle unlikely to affect the metabolism of other drugs that are substrates of this isoenzyme. Milk thistle + Benzodiazepines Milk thistle does not appear to affect the pharmacokinetics of midazolam. Evidence, mechanism, importance and management In a study 19 healthy subjects were given milk thistle 300 mg three times daily for 14 days (standardised to silymarin 80%) with a single 8-mg oral dose of midazolam on the last day. There was no change in the pharmacokinetics of midazolam, and milk thistle had no effect on the duration of midazolam-induced sleep. Milk thistle + Digoxin Milk thistle does not appear to affect the pharmacokinetics of digoxin. Clinical evidence In a study, 16 healthy subjects were given a single 400-microgram dose of digoxin before and on the last day of a 14-day course of a milk thistle extract (standardised to 80% silymarin) 300 mg three times daily. Digoxin is a Pglycoprotein substrate, and it had been suggested that milk thistle would therefore affect digoxin pharmacokinetics. Importance and management Direct evidence appears to be limited to one clinical study, which showed that milk thistle does not cause clinically relevant changes in digoxin pharmacokinetics. It would therefore appear that the dose of digoxin would not need to be adjusted in patients also given milk thistle. As digoxin is used as a probe substrate for P-glycoprotein this study also suggests that milk thistle is unlikely to affect the metabolism of other drugs that are substrates of this transporter protein. Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport. Milk thistle + Caffeine Milk thistle does not appear to affect the pharmacokinetics of caffeine. Evidence, mechanism, importance and management In a study in 12 healthy subjects, milk thistle 175 mg (standardised to silymarins 80%) given twice daily for 28 days had no significant effects on the metabolism of a single 100-mg dose of caffeine. Milk thistle + Chlorzoxazone Milk thistle does not appear to affect the pharmacokinetics of chlorzoxazone. Evidence, mechanism, importance and management In a study in 12 healthy subjects, milk thistle 175 mg (standardised to silymarins 80%) given twice daily for 28 days had no significant effects on the metabolism of a single 250-mg dose of chlorzoxazone. M Milk thistle + Irinotecan Milk thistle does not appear to affect the pharmacokinetics of irinotecan. Milk thistle Evidence, mechanism, importance and management A pharmacokinetic study was undertaken in 6 patients who were being treated with intravenous irinotecan 125 mg/m2 once weekly for 4 weeks, followed by a 2-week rest period. Four days before the second dose of irinotecan, a 14-day course of 200 mg milk thistle seed extract (containing silymarin 80%) three times daily was started. The pharmacokinetics of irinotecan and its metabolites did not differ from week 1 (no milk thistle), week 2 (4 days of milk thistle) to week 3 (12 days of milk thistle). The clinical study found that milk thistle may modestly delay the absorption of nifedipine with an apparent high intra-individual variability. However, as there was no considerable change in the pharmacokinetics or pharmacodynamic effects of nifedipine (blood pressure and heart rate), this is probably not clinically relevant. It would appear that the modest effects found in vitro do not translate in to a clinically relevant effect. Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Milk thistle + Metronidazole Silymarin (the active constituent of milk thistle) modestly reduces metronidazole levels. Evidence, mechanism, importance and management Silymarin (Silybon) 140 mg daily was given to 12 healthy subjects for 9 days, with metronidazole 400 mg three times daily on days 7 to 10. See Milk thistle + Benzodiazepines, page 294, and Milk thistle + Protease inhibitors, below. Study on the influence of silymarin pretreatment on metabolism and disposition of metronidazole. Milk thistle + Protease inhibitors Although some studies have found that milk thistle slightly lowers indinavir levels, it appears that this is a time-dependent effect rather than a drug interaction, since it also occurred in a control group in one study. The balance of evidence suggests that no important pharmacokinetic interaction occurs. In vitro studies suggest that silibinin does not affect the pharmacokinetics of ritonavir. Clinical evidence In a study in 16 healthy subjects, silymarin 280 mg was given 10 hours, and 90 minutes, before a 10-mg dose of nifedipine. This M 296 Milk thistle with pyrazinamide, milk thistle appears to increase the levels of the active metabolite, pyrazinoic acid. So far, this has only been shown in rats so determining the clinical relevance of this interaction is difficult. Nevertheless, because of the dose-related hepatotoxic adverse effects associated with pyrazinamide, it would be prudent to bear this possible interaction in mind in case of an unexpected response to treatment. Effect of silibinin on the pharmacokinetics of pyrazinamide and pyrazinoic acid in rats. Importance and management the currently available data suggest that milk thistle extract does not have an effect on the pharmacokinetics of indinavir (and possibly ritonavir), although this is not totally conclusive. The reduction in indinavir levels appears to be just a time-dependent effect rather than an effect of the milk thistle, but further study is needed with longer exposure to indinavir than just four doses. Evidence appears to be too slim to prohibit concurrent use, but until more is known it may be prudent to give milk thistle cautiously to patients taking indinavir. Effect of milk thistle on the pharmacokinetics of indinavir in healthy volunteers. Milk thistle and indinavir: a randomized controlled pharmacokinetics study and meta-analysis. Milk thistle + Ranitidine Silymarin, a major constituent of milk thistle, does not appear to affect the pharmackinetics of single-dose ranitidine. Evidence, mechanism, importance and management In a study in 12 healthy subjects, silymarin capsules (Sivylar) 140 mg three times daily for 7 days did not significantly affect the pharmacokinetics of a single 150-mg dose of ranitidine. Effect of silymarin on the oral bioavailability of ranitidine in healthy human volunteers. Milk thistle + Pyrazinamide the interaction between milk thistle and pyrazinamide is based on experimental evidence only. Experimental evidence In a study in rats,1 pyrazinamide and its active metabolite, pyrazinoic acid, were given after either long-term or short-term exposure to silibinin, the major active constituent of the silymarin flavonolignan mixture found in milk thistle. The first group of rats received intravenous silibinin 100 mg/kg for 3 days before an intravenous dose of pyrazinamide 50 mg/kg or pyrazinoic acid 30 mg/kg concurrently on the fourth day. The second group received intravenous silibinin 30 mg/kg 10 minutes before an intravenous dose of pyrazinamide 50 mg/kg or pyrazinoic acid 30 mg/kg. The maximum serum levels of pyrazinoic acid were increased by about 60% and 70% respectively. Mechanism It is thought that silibinin may inhibit xanthine oxidase, which is involved in pyrazinamide and pyrazinoic acid hydroxylation. While no pharmacokinetic changes were seen when milk thistle was given Milk thistle + Rosuvastatin Silymarin, a major constituent of milk thistle, does not appear to affect the pharmackinetics of single-dose rosuvastatin. Clinical evidence In a randomised study, 8 healthy subjects were given silymarin (Legalon) 140 mg three times daily for 5 days. Importance and management No particular precautions would appear to be necessary if patients decide to take milk thistle and rosuvastatin together. M Natural coumarins N Natural coumarins are widespread in herbal medicines and vegetables. Moreover, at present, there are no established interactions between warfarin and herbal medicines that have been attributed to the natural coumarin content of the herb. Even in the classic case of haemorrhagic death of livestock that led to the discovery of dicoumarol, it was the action of the mould on the natural coumarin in the sweet clover (melilot, page 290) that led to the production of the anticoagulant, so consumption of a spoiled product would seem to be necessary for this specific interaction to occur. This suggests that the occurrence of natural coumarins in dietary supplements or herbal medicines should not trigger immediate concern as regards interactions with anticoagulants. The information in this family monograph relates to the individual natural coumarins, and the reader is referred back to the herb (and vice versa) where appropriate. Others are more complex, such as the highly toxic aflatoxin B1, which is produced by microbial contamination of food crops with Aspergillus niger. They are mainly present in the two large plant families Rutaceae and Apiaceae, but occur in others. The Apiaceae family includes aniseed, page 33, asafoetida, page 39, celery, page 123, Chinese angelica, page 129, carrot, parsnip, and many other herbs and spices.
However bacteria and archaea are similar in which of the following order azithromycin 100mg, due to the mixed chemical nature of the exposures and generally insufficient information on possible exposure-response relationships antibiotic wipes azithromycin 500 mg sale, the human studies provide only limited evidence that exposed adults and infants exposed in utero or via breast feeding may have compromised their immune system rendering them unable to overcome infection antibiotics nephrotoxicity order azithromycin 500mg amex. Also antibiotic resistance usa today discount azithromycin 100mg amex, minimal immunological alterations were induced in infant monkeys that were orally exposed to a similar dose (0 bacteria helpful to humans cheap azithromycin 100mg. The results from cognitive assessment of this cohort are expected to be available in the near future bacteria vs archaea purchase azithromycin 500 mg online. Chloracne and other skin changes, and various hepatic alterations including increased serum levels of liver enzymes and lipids have been associated with occupational exposures. There are also reports of respiratory, gastrointestinal, hematological, skeletal, developmental, and neurological effects in exposed workers, but the evidence is not strong enough to conclusively establish cause-effect relationships. The epidemiologic studies of the contaminated fisheating populations and people exposed via the general environment raise concern for reproductive effects in adults and neurodevelopmental and immunological alterations in children of exposed parents, as discussed above in the Reproductive Toxicity, Developmental Toxicity, Neurotoxicity, and Immunotoxicity data need subsections. Many of these are prospective studies that have followed-up the children for many years and are expected to continue to do so in order to ascertain the duration and real life significance of these subtle alterations. Only one study was located that provided quantitative oral absorption data in a volunteer (Buhler et al. For other congeners, there was a trend for decreasing net absorption and/or increasing net excretion with increasing congener concentration in serum lipids. Similar congener specific, mass balance human studies are needed to confirm and extend these findings. While this approach is necessary to summarize data for publication, congener profiles for individuals are often never reported. Numerous factors, such as the analytical methods used by various labs for sample preparation and analysis, the type of human sample (milk, serum, plasma, adipose), sample size, year sample was collected, subject age, and exposure history are all critical to the detection and quantification of a specific congener in a given sample. Studies regarding distribution through the placenta after inhalation and dermal exposures were not available. Although information regarding metabolism following inhalation or dermal exposure is lacking, there is no reason to believe that other pathways would operate after exposure by these routes. Although data regarding excretion in animals after inhalation exposure were not located, there is no reason to suspect different patterns of excretion. However, these differences appear to be highly dependent on the specific congener or mixture studied. In addition, studies with human cell systems in vitro could help estimate metabolic rate constants for use in pharmacokinetic models. Identification of metabolites in humans and animals suggests that all species examined share some common biochemical reactions. Experimental data in animals indicate that fecal elimination is the main route of excretion (Bleavins et al. Analysis of the excreta of humans exposed in the workplace and near hazardous waste sites would provide information regarding biotransformation and elimination kinetics in humans. Monkeys and minks are the most sensitive species tested regarding dioxin-like effects, but pharmacokinetic data in minks are scant. However, the clinicopathologic picture in monkeys is more like humans than any other species. As these studies suggest, the monkey is more sensitive than humans on a dose basis. In experimental animals, however, administration of rice bran fiber reduced gastrointestinal absorption (Takenaka and Tarahashi 1991). Identification of additional substances that could prevent or delay absorption and that do not represent a toxic risk themselves would be valuable. There are no established methods for reducing body burden in humans, but a few reports have indicated that fasting may be effective (Imamura and Tung 1984). Thus, additional studies examining the feasibility of favoring metabolic pathways leading to the formation of nontoxic metabolites would be valuable. Data needs relating to developmental effects are discussed more extensively above in the Developmental Toxicity subsection. Continued monitoring of children from the Dutch, Lake Michigan, Lake Ontario prospective studies is expected with particular emphasis on evaluation of immune competence, thyroid function, and cognitive abilities. The benzene rings can rotate around the bond connecting them; the two extreme configurations are planar (the two benzene rings in the same plane) and the nonplanar in which the benzene rings are at a 90E angle to each other. The degree of planarity is largely determined by the number of substitutions in the ortho positions. The replacement of hydrogen atoms in the ortho positions with larger chlorine atoms forces the benzene rings to rotate out of the planar configuration. Thus, Aroclor 1242 is a chlorinated biphenyl mixture of varying amounts of mono- through heptachlorinated homologs with an average chlorine content of 42%. The exception to this code is Aroclor 1016, which contains mono- through hexachlorinated homologs with an average chlorine content of 41% (Hutzinger et al. This made them useful in a wide variety of applications, including dielectric fluids in transformers and capacitors, heat transfer fluids, and lubricants (Afghan and Chau 1989). The approximate weight percent of chlorobiphenyls in some commercial Aroclors is summarized in Table 4-4, and the congener composition of Aroclors is shown in Table 4-5. For example, a late production Aroclor 1254 lot (Aroclor 1254 "Late"), with greatly Table 4-1. Experimental values for the individual components were obtained from Hansch and Leo 1985. The impurities 2,3,7,8-tetrachlorodibenzofuran and 2,3,4,7,8-pentachlorodibenzofuran were found at concentrations of 0. The congeners reported are important due to their toxicity or because they occur in higher concentrations in the environment. Marketed worldwide under trade names such as Aroclor, Askarel, and Therminol, the annual U. Between 1957 and 1971, 12 different types of Aroclors, with chlorine contents ranging from 21 to 68% were produced in the United States. The manufacturing process for Aroclors involved the chlorination of biphenyl with anhydrous chlorine in the presence of a catalyst, such as iron filings or ferric chloride. Late production Aroclor 1254 (Aroclor 1254 "Late") was made by a two-stage chlorination procedure from 1974 to 1977. In the first stage, biphenyl was chlorinated to 42% chlorine content by weight as for Aroclor 1242 production. This was then fractionated to give a distillate that was sold as Aroclor 1016 and a residue that would have contained mostly the mono-ortho tetrachlorobiphenyls and higher homologs. While production records suggest that Aroclor 1254 "Late" represented <1% of the total Aroclor 1254 production, the availability of this lot during the final years of production resulted in the disproportionate use of Aroclor 1254 "Late" by standards suppliers and researchers into Aroclor 1254 toxicity (Brinkman et al. In 1974, the Monsanto Chemical Company produced slightly more than 40 million pounds (18 million kg) of Aroclor mixtures. Of the total volume of Aroclors sold in the United States for that year, the percentages of the market for each of the Aroclors were: Aroclor 1016, 64%; Aroclor 1242, 17. The production of capacitors and transformers involved filling them with Aroclors through a small hole in the unit and then sealing the hole. As of January 1979, Aroclors were no longer used in the production of capacitors and transformers. In order to ensure that the statutory requirements are met, the various proposed alternatives are evaluated using nine evaluation criteria that reflect these statutory requirements (U. The nine criteria are categorized into three groups: threshold criteria, primary balancing criteria, and modifying criteria. The primary balancing criteria include provisions for evaluating long-term effectiveness and permanence; the reduction of contaminant toxicity, mobility, or volume; and short-term effectiveness for adverse health effects from human exposure, implementability, and cost. While the primary balancing criteria are used to weigh major tradeoffs among the proposed alternatives, and the modifying criteria are not taken into account Table 5-2. An evaluation of the applicability of oxy-fuel technology to waste incineration conducted by Baukal et al. The thermal desorption and solvent extraction technologies, though not designed to destroy the contaminants, indirectly separate the contaminants from a solid matrix and concentrate them into smaller volumes of treatable oily residues. The removal efficiencies of these technologies when applied to three of the river sediments tested ranged from 96 to 99%. Zhang and Rusling (1995) investigated electrochemical catalytic dechlorination as a method for decontaminating soils. The study achieved a 94% dechlorination level using a lead cathode and a micro emulsion of didodecylmethylammonium bromide, dodecane, and water for soils containing 6. Of these sites, 499 are located within the United States and 1 is located in the U. Aroclors are no longer produced in the United States, except under exemption (see Section 5. Higher chlorinated congeners are more likely to sorb, while lower chlorinated congeners are more likely to volatilize (Eisenreich et al. Volatilization from soil appears to be an important loss mechanism; it is more important for the lower chlorinated congeners than for the higher chlorinated congeners (Hansen 1999). Chinook salmon sampled from Lakes Ontario and Huron from 1991 to 1994 had mean concentrations of 0. Exemptions may be granted to individual petitioners for use with optical microscopy, and for research and development (see Section 5. Higher chlorinated congeners are more likely to sorb, while lower chlorinated congeners are more likely to volatilize. Volatilization from soil appears to be an important loss mechanism; it is more important for the lower chlorinated congeners than for the higher chlorinated congeners. These fluxes are the highest in summer as a result of warmer temperatures (Hoff et al. Contaminated sediments exposed directly to the atmosphere during water level changes. They found that the overlying air was enriched in the more volatile, lower molecular weight congeners compared to the deposited sediment, which suggests that volatilization was the major transport process out of the sediment for these congeners. The average fluxes from sediments were between 2 and 100 times more than the flux coming down the river, and clearly dominated other fluxes from direct atmospheric deposition and waste water treatment plant discharges. However, the more water soluble, lower chlorinated (and ortho-rich) congeners are predominantly in the dissolved state in the water column and can readily partition into the vapor phase. Percentage of Loss of Polychlorinated Biphenyls from the Great Lakes Waters Outflow to other bodies of water 2. Bioconcentration is defined as uptake of a chemical from water alone; and bioaccumulation is the result of combined uptake via food, sediment, and water. The differences in congener retention in organisms apparently accounts for the differences in Table 6-3. As a result, bioaccumulation by fish is several orders of magnitude higher in this zone (Sodergren et al. As previously observed for bioaccumulation, differences in retention also account for differences in congener biomagnification in higher trophic levels. The tendency to leach will be greatest among the least chlorinated congeners and is expected to be greatest in soil with low organic carbon (Sklarew and Girvin 1987; Strek and Weber 1982a). Lawrence River solids originally contaminated with Aroclor 1248, several ortho-chlorinated congeners were preferentially lost by volatilization, which could be positively correlated with water loss by vaporization. For the two vegetated areas, the volatilization rate appeared to be reduced by organic matter from both living and dead vegetation. The lower chlorinated (and ortho-enriched) congeners, which have the highest concentrations in the atmosphere, are the most efficiently scavenged by terrestrial vegetation by vapor-to-plant transfer (Jones and Duarte-Davidson 1997; Thomas et al. Biodegradation in the environment, although slow, occurs under both aerobic and anaerobic conditions. In sediments, aside from the aerobic surface layer, anaerobic microbial degradation will be primarily responsible for transformation, particularly of the more highly chlorinated congeners. Aerobic biodegradation in soil, surface water, and sediments is limited to the less chlorinated congeners. The calculated tropospheric lifetime values for this reaction increases as the number of chlorine substitutions increases. In all cases, the ring with the greatest degree of chlorination is the primary ring where dechlorination occurs. These dechlorination reactions have been reported to proceed by the loss of chlorine in the order of ortho>para>meta (Barr et al. The estimated photolysis half-lives of mono- through tetrachlorobiphenyls with summer sunlight at a shallow water depth (<0. These congeners are also more likely to biodegrade under aerobic conditions (Bailey et al. The biodegradation of Aroclor 1221 proceeded rapidly in unfiltered lake water after a 4-day lag phase; within 1 month, the original mixture was completely degraded into metabolites of lower molecular weight (Wong and Kaiser 1975). However, Aroclor 1260 was not degraded over a 12-week period in three different unfiltered natural water samples (Oloffs et al. In general, these results are similar to those reported in aerobic soil and sediment studies where mono-, di-, and trichlorobiphenyl structures are fairly readily biodegraded, biphenyl rings containing five or more chlorine substituents are considered to be persistent, and tetrachlorobiphenyl congeners exhibit an intermediate persistence (Abramowitz 1990; Alcock et al. Biodegradation rates in marine water may be slower than those reported in freshwater.
