Professor of Medicine and Pathology and Laboratory Medicine
Director, Francis Owen Blood Research Laboratory
Division of Cardiology
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Interactions overview An isolated case of lithium toxicity has been reported in a patient who took a herbal diuretic containing bearberry among other ingredients medicine 750 dollars order rumalaya 60pills without a prescription, see under Parsley + Lithium medications questions purchase 60 pills rumalaya visa, page 305 treatment meaning 60pills rumalaya with visa. For information on the interactions of individual flavonoid constituents of bearberry medicine lock box cheap rumalaya 60 pills otc, see under flavonoids medicine 95a cheap rumalaya 60 pills without a prescription, page 186 medicine queen mary cheap rumalaya 60pills online. Urinary excretion and metabolism of arbutin after oral administration of Arctostaphylos uvae ursi extract as film-coated tablets and aqueous solution in healthy humans. Urinary excretion of arbutin metabolites after oral administration of bearberry leaf extracts. In vitro activity of uva-ursi against cytochrome P450 isoenzymes and P-glycoprotein. Use and indications Bearberry leaves and preparations are traditionally used for urinary tract infections. The use of arbutin and hydroquinone as skin-whitening agents has been investigated. However, it is rapidly conjugated in the urine, mainly as hydroquinone glucuronide and hydroquinone sulfate. Bearberry + Lithium For mention of a case of lithium toxicity in a woman who had been taking a non-prescription herbal diuretic containing corn silk, Equisetum hyemale, juniper, buchu, parsley and bearberry, all of which are believed to have diuretic actions, see under Parsley + Lithium, page 305. Bee pollen consists of flower pollen and nectar from male seed flowers, which is mixed with secretions from a worker honey bee. Note that there are products made from pollen alone, such as Cernilton (Rye grass pollen), which will not be dealt with in this monograph. Use and indications Bee pollen has been taken for prostate enlargement and to reduce the risk of atherosclerosis and hypertension, and to improve cognition. It should be avoided by people allergic to bee stings and to pollen because of the risk of a hypersensitivity reaction. Constituents the constituents of bee pollen depend to some extent on the flower species from which it has been harvested. It usually contains phytosterols, essential fatty acids including linoleic and alpha-linolenic acids, flavonoids and other polyphenols, minerals, and small amounts of B vitamins and vitamin C. Coumaroyl spermine and spermidine derivatives have been isolated from Brazilian bee pollen. It has been used for many conditions, such as amoebic dysentery and diarrhoea, inflammation and liver disease. Berberine is also said to possess some antiepileptic, uterine stimulant and hypotensive effects, and is slightly sedative. Interactions overview Although a number of studies have used conventional drugs to study berberine metabolism, data on potentially clinically relevant interactions is sparse: the most significant interaction of berberine appears to be its potential to increase ciclosporin levels. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Pharmacokinetics Berberine appears to undergo significant hepatobiliary excretion, including metabolism by cytochrome P450. Its metabolism in rats was partially affected by a known experimental inhibitor of cytochrome P450 isoenzymes. Experimental evidence the effect of berberine was investigated using two experimental anxiety models in the mouse. Berberine showed anxiolytic effects in these models at a dose of 100 mg/kg, and sedative effects at a dose of 500 mg/kg. Berberine was found to enhance the anxiolytic effects of buspirone in the elevated plus-maze test, whereas the anxiolytic effects of berberine were not affected by diazepam. Importance and management the doses of berberine given in this study were extremely large, compared with those used in clinical studies in humans. Animal studies suggest that ciclosporin may also affect the handling of berberine possibly by inhibiting P-glycoprotein, therefore affecting its intestinal absorption and its distribution into the bile and liver. Importance and management Although the increase in ciclosporin levels is not sufficiently severe to suggest that the concurrent use of berberine should be avoided, it may make ciclosporin levels less stable. If concurrent use is undertaken, ciclosporin levels should be well monitored, and the dose of ciclosporin adjusted accordingly. Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients: clinical and pharmacokinetic study. The effects of berberine on the pharmacokinetics of ciclosporin A in healthy volunteers. Berberine + Ciclosporin Berberine appears to increase the bioavailability and trough blood levels of ciclosporin. Animal studies suggest that ciclosporin may affect the intestinal absorption and elimination of berberine possibly by inhibiting P-glycoprotein. Clinical evidence A study in 6 kidney transplant recipients looked at the effects of berberine on the pharmacokinetics of ciclosporin. The patients were taking ciclosporin 3 mg/kg twice daily for an average of 12 days before berberine 200 mg three times daily for 12 days was added. The peak ciclosporin level was decreased but this was not statistically significant. Creatinine clearance was not significantly altered, and no serious adverse effects were reported. Six subjects given a single 6-mg/kg dose of ciclosporin daily found that berberine 300 mg twice daily, taken for 10 days before the dose of ciclosporin, had no significant effects on the pharmacokinetics of ciclosporin. Berberine + Hyoscine (Scopolamine) the interaction between berberine and hyoscine (scopolamine) is based on experimental evidence only. Experimental evidence Berberine 100 and 500 mg/kg, given orally for 7 to 14 days significantly improved hyoscine-induced amnesia in rats, measured using a step-through passive avoidance task. This antiamnesic effect of berberine was completely reversed by hyoscine methobromide, implying that the antiamnesic action of berberine may be through the peripheral rather than central nervous system. Importance and management the experimental evidence for this interaction is very limited and there appears to be no data to suggest that berberine may improve memory or reverse the effects of drugs that affect memory, such as hysocine, in humans. This is unlikely to be a clinically significant 60 Berberine Experimental evidence An in vitro study found that pre-treatment with berberine blocked the anticancer effects of paclitaxel in six cancer cell line cultures (oral cancer, gastric cancer and colon cancer). Effect of long-term administration of berberine on scopolamine-induced amnesia in rats. B Berberine + Paclitaxel the interaction between berberine and paclitaxel is based on experimental evidence only. Importance and management this appears to be the only published study of an antagonistic effect between berberine and paclitaxel. Further study is required to confirm these in vitro results, and to explore their clinical relevance. Berberine modulates expression of mdr1 gene product and the responses of digestive track cancer cells to paclitaxel. It has some antiepileptic, uterine stimulant and hypotensive effects and is slightly sedative, as are jatrorrhizine and palmatine. Constituents the root and stem of all species contain isoquinoline alkaloids such as berberine, berbamine, jatrorrhizine, oxyberberine, palmatine, magnoflorine, oxyacanthine and others. Pharmacokinetics No relevant pharmacokinetic data found specifically for berberis, but see berberine, page 58, for information on this constituent of berberis. For information on the interactions of one of its constituents, berberine, see under berberine, page 58. Use and indications Used for many conditions, especially infective, such as amoebic dysentery and diarrhoea, inflammation and liver 61 Betacarotene B Types, sources and related compounds Provitamin A. As betacarotene intake increases, vitamin A production from the carotenoid is reduced. Use and indications Betacarotene is a carotenoid precursor to vitamin A (retinol). It is a natural pigment found in many plants including fruit and vegetables (such as carrots) and is therefore eaten as part of a healthy diet, and is also used as a food colouring. Betacarotene supplements are usually taken for the prevention of vitamin A deficiency and for reducing photosensitivities in patients with erythropoietic protoporphyria. It is also used for age-related macular degeneration and has been investigated for possible use in cardiovascular disease and cancer prevention. Interactions overview Orlistat reduces betacarotene absorption, heavy long-term alcohol intake may interfere with the conversion of betacarotene to vitamin A, and the desired effect of betacarotene supplementation may be reduced by colchicine and omeprazole. Betacarotene reduces the benefits that combined simvastatin and nicotinic acid have on cholesterol, and reduces ciclosporin levels. Combined use with colestyramine or probucol modestly reduces dietary betacarotene absorption. Clinically relevant interactions are unlikely between betacarotene and tobacco, but note that smokers are advised against taking betacarotene. For the interactions of betacarotene with food or lycopene, see Lycopene + Food, page 280, and Lycopene + Herbal medicines; Betacarotene, page 280. Pharmacokinetics Betacarotene is the most studied carotenoid of the hundreds that exist in nature. It is a fat-soluble precursor of vitamin A (retinol) and a large part of the metabolism to vitamin A takes place in the gastrointestinal mucosa where its absorption may be sensitive to changes in gastric pH, see proton pump inhibitors, page 64. This could be a contributing factor 62 Betacarotene 63 Betacarotene + Alcohol Heavy consumption of alcohol may interfere with the conversion of betacarotene to vitamin A. When betacarotene was stopped, its clearance was delayed in the baboons fed alcohol. It has therefore been suggested that alcohol interferes with the conversion of betacarotene to vitamin A. It appears that the long-term intake of alcohol causes some changes in betacarotene disposition, and it would therefore seem sensible to try to limit alcohol intake if betacarotene supplementation is necessary. Effects of supplemental -carotene, cigarette smoking, and alcohol consumption on serum carotenoids in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Interaction of ethanol with -carotene: delayed blood clearance and enhanced hepatotoxicity. Alcohol, vitamin A, and -carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Importance and management the clinical significance of this study is unclear as there appear to be no published case reports of any adverse effects due to this interaction. Furthermore, a decrease in ciclosporin levels of 24% is fairly modest, and other studies have found that vitamin C 1 g daily and vitamin E 300 mg daily may slightly decrease ciclosporin levels, so the potential for a clinically significant interaction with betacarotene alone is unclear. However, until more is known it may be prudent to consider an interaction with betacarotene if a sudden or unexplained reduction in stable ciclosporin levels occurs. More study is needed, particularly with regard to the concurrent use of standard, commercially available, multivitamin preparations. Effects of antioxidant supplementation on blood cyclosporin A and glomerular filtration rate in renal transplant recipients. B Betacarotene + Cimetidine An interaction between betacarotene and cimetidine is based on experimental evidence only. Experimental evidence In an animal study, rats were given intragastric alcohol to induce mucosal damage. When the rats were pretreated with betacarotene 1 mg/kg, the number of mucosal lesions was decreased by 63%. However, when cimetidine 50 mg/kg was given with the betacarotene, 30 minutes before the alcohol, the damaging effects of the alcohol appeared to be enhanced. Importance and management this is a relatively old study and there do not appear to be any clinical reports in the literature. Furthermore the dose of betacarotene used is roughly 10-fold greater than the recommended daily intake of betacarotene. Betacarotene + Ciclosporin A study in 10 kidney transplant recipients found that an antioxidant vitamin supplement containing betacarotene modestly reduced ciclosporin blood levels. Clinical evidence A randomised placebo-controlled study, in 10 kidney transplant recipients taking ciclosporin, found that the addition of an antioxidant vitamin supplement for 6 months containing vitamin C 500 mg, vitamin E 400 units and betacarotene 6 mg daily reduced the ciclosporin blood level by 24%. An associated improvement in renal function, indicated by an increase in glomerular filtration rate of 17%, was also seen and may have been associated with reduced ciclosporin levels. Betacarotene + Colchicine the desired effect of betacarotene supplementation may be reduced in those taking colchicine. Colchicine causes reversible malabsorption in the gastrointestinal tract by disturbing epithelial cell function 64 Betacarotene Importance and management There appears to be only one study investigating the effects of betacarotene on treatment with lipid lowering drugs; however, the study was well designed, long term, and large. Antioxidant supplementation including betacarotene appears to suppress the beneficial effects of the combined treatment of simvastatin and nicotinic acid on high-density lipoprotein-cholesterol, higher levels of which reduce the risk of major cardiovascular events. The authors suggest that their results indicate that the use of antioxidants to prevent cardiovascular events should be questioned. What this means for patients taking lower therapeutic doses of betacarotene (recommended daily intake is about 6 mg daily, about one-quarter of the dose used in the study) is unclear. Therefore, until more is known it would seem prudent to avoid concurrent use, unless there is a clear defined clinical need for betacarotene supplementation. The use of colestyramine and probucol appears to lower betacarotene levels, but the clinical importance of this does not appear to have been established. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. All these factors could have an effect on the absorption of betacarotene, which largely takes place in the gastrointestinal mucosa and the distribution of which is dependent on the presence of lipoproteins. B Importance and management the evidence for a possible interaction between betacarotene and colchicine is limited to two relatively old studies. While supplemental betacarotene absorption appears to be reduced, betacarotene ingested as part of the normal diet appears to be unaffected. Based on these two findings, and the fact that there is large interindividual variation in betacarotene absorption, it is difficult to recommend a clinical course of action other than to be aware that the desired effect of betacarotene supplementation may be reduced in those taking colchicine. Gastrointestinal effects of long-term colchicine therapy in patients with recurrent polyserositis (familial Mediterranean fever).
There was the creation of a new research area in regard to the identified gene medications vaginal dryness generic 60pills rumalaya with mastercard, and this moved on to the study of all associated genes xanax medications for anxiety safe rumalaya 60 pills, mechanistic studies and studies in higher order mammals symptoms 0f diabetes discount rumalaya 60pills with amex, including humans asthma medications 7 letters buy cheap rumalaya 60 pills line. The transgenic mouse used in this study was one of the first applications of knockout technology in Australia and has since been used in further studies k-9 medications cheap rumalaya 60pills otc. The experimental use of these animals has so far resulted in a number of publications treatment for vertigo cheap 60pills rumalaya. Over the next year this technology will be increasingly used in new targeting strategies. Professor Harvey was also invited to present his work at a number of conferences and other scientific meetings. When they first started the research it was a new field and so they built connections through the muscle field and cardiac field and then into the cardiology field. It could be argued that the success of this project helped to firm up the idea of using animal models for development (and possibly other areas of research), but this would have been part of a broader body of work. It certainly did lead to new areas of research that would be of influence, such as looking for gene defects related to the developmental genes studies. Some of these mutations have now been established as screening tools for congenital heart defects in families with a history of the disease. Downstream application to clinical practice has also occurred in genetic screening in congenital heart disease, but this has been very recent. Genetically modified mice and rats are currently the only animal models that allow researchers to mimic human conditions of genetic disorders on a molecular level and represent the most sophisticated and valuable tools in functional genomics and drug target validation. Parsons said, `He enjoys the synergy of collaborations and I think he encourages that in his postdocs. This led to the broader studies in humans and others that led to the prenatal genetic testing. There was identification of the potential for the knowledge and techniques to be applied elsewhere in basic research but not more broadly. There may have been potential for mentoring and support for broader dissemination and greater recognition of the broader implications and potential. The initial investment in the project is still being realised, with Professor Harvey continuing to be associated with the National Heart Foundation of Australia. Table 13-2 shows, in point form and by impact category, some of the impacts, described more fully above, that have emerged from this grant. Grant Application, Application Form for Grant-in-aid Research - Senior Research Fellowship, the role of the regulatory gene, Mlx1, in cardiac development and disease, and the creation of animal models for myocardial dysfunction, 1992, grant reference G92M3633, held in the National Heart Foundation of Australia archives. Bild, `Prevalence of Hypertrophic Cardiomyopathy in a General Population of Young Adults. Some neurons die within minutes of a stroke, while others take several days to die, causing permanent brain damage. Although little can be done for neurons that die immediately following a stroke, it was believed to be possible to rescue the neurons that take several days to die. Doing so required an understanding of the mechanisms that cause this delayed neuronal death. This study was led by Dr Leif Hertz and two co-applicants, Dr Bernhard Juurlink and Dr Jerome Yager. Many affected infants will suffer permanent brain damage, manifested as cerebral palsy, mental retardation and seizures, as a consequence of nerve cell death. Although little can be done for the neurons that die within minutes of a stroke, researchers thought that it should be possible to rescue the neurons that take several days to die. Specifically, astrocytes are characteristic star-shaped glial cells in the brain and spinal cord. The research team believed that many neurons die following a stroke because of injury to astrocytes, so the objective of this research was to better understand the effect stroke has on immature and mature astrocytes and how astrocyte injury leads to neuron death. Evidence had indicated that some of these differences are related to changes in astrocyte function with maturation. The research team had demonstrated that mature astrocytes suffer more damage during reperfusion following hypoxia than during the hypoxic insult (Sochocka et al. Leading up to 1993, although the vast majority of studies in the area of cerebral ischaemia had focused directly on the neurons, evidence was accumulating that astrocytic impairment was of functional importance and that primary effects on astrocytes may lead to delayed neuronal death. Astrocytes accumulate neuroactive compounds like potassium and glutamate from the extracellular fluid. Furthermore, the neuropathologic consequences of such insults differed in distribution and extent of damage. The team believed that the results from this study could help develop strategies for medical therapies in the treatment and prevention of stroke-related neuronal death and complications specific to different ages. This information was expected to have a direct influence on the development of agents or therapeutic interventions specific for patients with strokes, whether such individuals are premature infants or elderly people. Other comments made regarding impacts, the research climate, and so on, have been taken at face value. There was little general scientific interest in astrocytes at the time because people associated them with glue (they are also known as astroglia, which translates to nerve glue). In Denmark, Hertz was working on cultured cells in a biochemistry laboratory in which work was limited by a lack of tissue culture expertise. This instigated his move to the Department of Anatomy at the University of Saskatchewan in 1974, where he and his colleagues were able to establish the necessary cultures, including astrocytes and neuronal cultures. This means that a neuron cannot make glutamate and must depend on astrocytes to do so. In 1975, when he joined the Department of Anatomy, Hertz met and started to collaborate with Dr Juurlink. Juurlink, a co-applicant on the grant of interest, was well established in performing cell-culture techniques. At that time, his research was not related to stroke but was basic function research. He started working within the area of stroke as a result of collaboration with Dr Shuaib, who was very interested in stroke and was the driving force in setting up the Saskatchewan Stroke Research Center, a coalition of researchers interested in stroke, which was funded by the Saskatchewan Health Board. In addition, a key publication in the early 1980s by Fred Plum indicated that if a stroke is relatively mild, selected neuronal cell death may occur (Plum, 1983). It is the converse of glutamate, which is the primary excitatory neurotransmitter in the brain. All of the methods were well established, except for the measurement of intracellular calcium, which proved to be very complicated. It was also noted that expression of c-fos is not necessarily a marker of injured cells, and its evaluation 24 hours after the insult was felt, by the reviewers, to be too late to see a past effect, which usually occurs much earlier. All reviewers commented on the lack of experimental data, as well as providing an evaluation of the pitfalls of the in-vitro assays. Table 14-1 Research Costs 1993-1994 (Can$) 41,418 600 5,000 18,700 11,000 76,718 1994-1995 (Can$) 43,489 -5,500 20,570 12,100 81,659 Fiscal year Technician (salary and benefits) Equipment (filters to adapt cytofluorometer to measure intracellular pH) Experimental animals (newborn and pregnant mice) Materials and supplies Other (anatomy facilities, travel and publication costs) Total 14. The production costs for the large amount of cultures needed for this study were high, especially because of the strict requirement for aseptic technique and conditions. He was a professor in the Department of Anatomy until 1979, after which he moved to the Department of Pharmacology, where he proceeded to lead an effective and active cell-culture laboratory for almost 20 years. Two co-applicants were listed on the grant: Dr Jerome Yager and Dr Bernhard Juurlink. Yager, a clinician, was an assistant professor in paediatrics at the Royal University Hospital in Saskatchewan and a member of the stroke research team. He was concurrently investigating hypothermia, perinatal hypoxic ischaemia and astrocytes. Juurlink, a biologist, worked in the Department of Anatomy at the University of Saskatchewan and was experienced in cell-culture techniques. He had a research interest in the survival of motor neurons and ischaemic events in cell cultures. His contribution to the team was in relation to the developmental-cell biological aspects of the studies. As one reviewer mentioned in the Scientific Review Committee Report, there was `no doubt that these investigators have the necessary resources, experience and enthusiasm to perform. Drs Juurlink, Yager and Hertz were all members of the Saskatchewan Stroke Research Center at the university. It was written in the application that Hertz and Juurlink were to dedicate approximately 35 percent of their time to the centre. One, Mrs Dunlop, a part-time technician, was said to be a highly skilled tissue-culture technician who would prepare and maintain most of the cultures used in the project. The other, Mr Reichert, a full-time technician, was tasked mainly with performing the biochemical analyses on the cultures and assisting with setting up the cultures. The research also confirmed that young astrocytes survive better with substrate deprivation. Juurlink, `Correlation Between Content of High-Energy Phosphates and Hypoxic-Ischemic Damage in Immature and Mature Astrocytes`, Developmental Brain Research, Vol. In the first article listed above, Juurlink and Hertz demonstrated that both astrocytes and cerebellar granule cell neurons die during an ischaemic insult only when there is complete loss of mitochondrial membrane potential (Juurlink and Hertz, 1993). The duration of ischaemia was three hours in cerebellar granular neuronal cell cultures and six hours in cortical neurons. The team observed that hypothermia protected both granular and cortical neurons, which suggests that, similar to the findings with astrocytes, the protective effects of hypothermia are evident in neuronal cell cultures from the cerebellum and cerebral cortex. Glutamate concentrations were measured in the incubation media at the end of the metabolic insults. Astrocytes were very resistant to hypoxia but less resistant to simulated ischaemia; under both conditions, the glutamate concentrations in the media remained low. Cerebral cortical neurons were almost equally susceptible to damage by hypoxia and simulated ischaemia, although hypoxia had a faster deleterious effect on some of the neurons and simulated ischaemia during a long-term insult (nine hours) killed all neurons, whereas a non-negligible neuronal subpopulation survived nine hours of hypoxia. Neuronal cell death after longterm hypoxia (but not after simulated ischaemia) was correlated with high concentrations of glutamate in the incubation media. In 1995, Hertz, Yager and Juurlink published their findings from studies in which astrocyte cultures prepared from newborn mouse neopallium were grown for either one or three weeks (representing, respectively, immature and mature astrocytes) and then exposed to deprivation of substrate (glucose and amino acids) for up to 48 hours (Hertz, Yager and Juurlink, 1995). In the mid-1990s, it was known that extracellular concentrations of glutamate and potassium ions increase during vascular insults in the brain, such as a stroke (Huang, Sochocka and Hertz, 1997). It was also well known that an increase in glutamate contributes to the death of neuronal cells at an earlier time than they would have succumbed to energy deprivation (Huang and Hertz, 1994). The origin of the released glutamate was unknown and cannot easily be studied in the brain in vivo. Huang, Sochocka and Hertz (1997) had shown through cell culture studies that the neuronal rate of formation of glutamate from glutamine is substantially increased during anoxia, especially in glutamatergic neurons. Phenylsuccinate, a compound that decreases formation of glutamate from glutamine in glutamatergic neurons, counteracts the increase in glutamate formation and, by doing so, improves cell survival (Huang and Hertz, 1995). Astrocytes in neuronalastrocytic co-cultures were found to protect against anoxic neuronal damage to some extent by accumulating glutamate and thus keeping the extracellular glutamate concentration lower than in isolated neuronal cultures (Hertz, 2003). The article carries on to say that although astrocytes may live longer during energy deprivation, they will eventually perish, mainly as a result of compensatory mechanisms during reperfusion. Astrocytic demise, in turn, damages the neurons due to insufficient glutamate uptake. Hertz highlights that, under some conditions, including perinatal brain ischaemia, pre-ischaemic hyperglycaemia can be neuroprotective, while hyperoxia after the insult is damaging both in the mature and immature brain. His students who participated in the studies, Rong Huang and Liang Peng, also conducted poster presentations at various conferences and meetings. Presentations were aimed at academics and other researchers, and although non-academics may have attended, they were not the primary audience. Two of these publications were indexed in Web of Science and received 21 citations in total, giving a relative citation impact of 1. Dr Hertz feels that papers have become the most effective method of dissemination since the 1990s, when literature searches became more common due to the internet. Prior to the internet, researchers would have had to consult electronic files or books in the library. This research also fed into the training of students at the graduate and undergraduate level.
Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation symptoms 8 dpo order rumalaya 60pills amex. Controlled vitamin K content diet for improving the management of poorly controlled anticoagulated patients: a clinical practice proposal symptoms nausea headache fatigue purchase rumalaya 60pills free shipping. Constituents Aloe vera gel is contained in the mucilaginous tissue that is found in the inner leaf medicine ketoconazole cream discount rumalaya 60pills online, and should not be confused with aloes treatment quality assurance unit order rumalaya 60 pills on line, page 27 medications cheap rumalaya 60 pills on-line, which is the latex stored in tubules along the leaf margin treatment resistant schizophrenia rumalaya 60 pills generic. Aloe vera gel may be produced by a handfilleted technique to remove the inner leaf, or by a whole-leaf extraction process where the aloes constituents (anthraquinones) are now usually subsequently removed. The principal constituents of the gel are polysaccharides consisting mainly of polymannans, of which acemannan is the major one. Other constituents include glycoproteins such as aloctins, and various carboxypeptidases, sterols, saponins, tannins, organic acids, vitamins and minerals. It is reported to possess anti-inflammatory, antitumour, immunomodulatory and antibacterial properties. Internally, aloe vera is thought to be immunostimulatory and to have mild analgesic, antioxidant and antidiabetic effects. Interactions overview Aloe vera contains only traces of anthraquinone glycosides, and would therefore not be expected to have any of the interactions of aloes, page 27, or similar herbal medicines, which occur, or are predicted to occur, as a result of their anthraquinone content. Aloe vera may have blood-glucose-lowering properties and may therefore be expected to interact with conventional drugs that have the same effect. Aloe vera appears to enhance the absorption of some vitamins but the clinical significance of this is not clear. Use and indications Aloe vera is used topically to aid wound healing from cuts 24 Aloe vera 25 Aloe vera + Antidiabetics Aloe vera juice reduces blood-glucose levels in patients with diabetes taking glibenclamide. Clinical evidence In placebo-controlled clinical studies, aloe vera juice (80%), one tablespoonful twice daily for 42 days, reduced blood-glucose in patients with diabetes, either taking glibenclamide,1 or not taking oral antidiabetic drugs,2 from an average of 14 to 16 mmol/L down to 8 mmol/L over a period of 6 weeks. However, it should be noted that, in the study in patients taking glibenclamide, there was, unexpectedly, no response to the use of glibenclamide alone. In these studies, the aloe vera juice (80%) was prepared from aloe gel and additional flavours and preservatives. Experimental evidence There is extensive literature (not cited here) on the possible bloodglucose-lowering effect of various extracts of aloe vera in animal models of diabetes, with some studies showing an effect and others not. Importance and management It seems possible that some oral preparations of aloe vera might have a clinically important blood-glucose-lowering effect. It might therefore be prudent to increase the frequency of blood-glucose monitoring if patients taking antidiabetic medication wish to try oral aloe vera preparations. The authors suggest that a possible interaction between sevoflurane and aloe vera contributed to the excessive bleeding seen. Experimental evidence Aloe vera gel extracts inhibited prostaglandin synthesis in vitro,2 and might therefore have antiplatelet activity. Mechanism Sevoflurane can inhibit platelet aggregation by inhibiting thromboxane A2, and aloe vera affects prostaglandin synthesis, which may also impair platelet aggregation. Therefore additive antiplatelet effects may have contributed to the excessive bleeding. Perioperative considerations in the management of the patient taking herbal medicines. A Aloe vera + Vitamins Aloe vera might delay, and enhance, the absorption of vitamin C and vitamin E. However, this difference was not statistically significant: it was attributed to the large interindividual differences. There was a second maximum plasma ascorbate level at 8 hours with the gel, and plasma ascorbate was still detectable at 24 hours, suggesting that aloe vera gel might delay, as well as enhance, absorption. Conversely, aloe vera whole leaf extract 60 mL had no significant effect on the absorption of vitamin C. However, the only statistically significant difference was the increase in plasma tocopherol at 8 hours, which occurred with both aloe vera extracts. The time to maximum level was delayed from 4 hours to 8 hours for the gel and to 6 hours for the leaf extract, suggesting that aloe vera might delay, as well as enhance, absorption. Mechanism the authors suggest that the vitamins may be protected from degradation in the intestine by flavonoid antioxidants in the aloe Aloe vera + Sevoflurane An isolated case report tentatively attributed increased surgical bleeding to the concurrent use of aloe vera and sevoflurane. Clinical evidence A 35-year-old woman, who had taken four aloe vera tablets (exact constituents and dose unknown) daily for 2 weeks before undergoing a procedure to excise a haemangioma from her left thigh, lost more than double the amount of blood estimated before surgery. Effect of Aloe vera preparations on the human bioavailability of vitamins C and E. A vera extracts and by polysaccharides that may bind to the vitamins, delaying and increasing their absorption. Use and indications Aloes has mainly been used internally as a laxative (although, note that this use has generally been superseded) and, in low concentrations, as a flavouring ingredient in food and drink. Pharmacokinetics the anthraquinone, emodin, is present in aloes (and similar plants) principally as the inactive glycoside. It travels through the gut, and is then metabolised by microflora to produce the active aglycone emodin, some of which is absorbed. Constituents Not to be confused with Aloe vera, page 24, which is the gel contained in the mucilaginous tissue that is found in the inner leaf. Aloes is derived from the latex that is stored in tubules along the margin of the leaf. When the outer leaf is cut, latex exudes from the leaf and this exudate, when dried, is aloes. Anthraquinone glycosides are major components of aloes and include barbaloin, a glycoside of aloe-emodin to which it may be standardised, and minor glycosides such as aloinosides A and B. Aloe-emodin, chrysophanol, chromones including aloesin, aloeresin E, isoaloeresin D and furoaloesone are also present in small amounts, as are resins. Interactions overview Although aloes have been predicted to interact with a number of drugs that lower potassium levels (such as the corticosteroids and potassium-depleting diuretics), or drugs where the effects become potentially harmful when potassium is lowered (such as digoxin), there appears to be little or no direct evidence that this occurs in practice. Biotransformation of the anthraquinones emodin and chrysophanol by cytochrome P450 enzymes. Consider also Senna + Digitalis glycosides, page 350, for the effects of anthraquinones on digoxin absorption. A Aloes + Corticosteroids Theoretically, the risk of hypokalaemia might be increased in patients taking corticosteroids, who also regularly use, or abuse, anthraquinone-containing substances such as aloes. Clinical evidence Chronic diarrhoea as a result of long-term use, or abuse, of stimulant laxatives such as aloes can cause excessive water and potassium loss; this has led to metabolic acidosis in one case. The effect of the over-use of aloes combined with systemic corticosteroids is not known, but, theoretically at least, the risk of hypokalaemia might be increased. Although this is mentioned in some reviews2 there do not appear to be any reports describing clinical cases of this effect. Mechanism In theory the additive loss of potassium, caused by anthraquinonecontaining substances and systemic corticosteroids, may result in hypokalaemia. Importance and management the interaction between aloes and corticosteroids is theoretical, but be aware of the potential in patients who regularly use, or abuse, anthraquinone-containing substances such as aloes. Aloes + 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 aloes. Chronic diarrhoea caused by long-term use, or abuse, of stimulant laxatives such as aloes, may also lead to excessive water loss and potassium deficiency. This interaction is sometimes mentioned in reviews;1,2 nevertheless, there is little, if any, direct evidence. There appears to be one case describing a myopathic syndrome related to potassium deficiency (potassium level 1. However, even this case may not have occurred as a result of an interaction as the patient also had gastroenteritis, causing profuse diarrhoea. Aloes + Digitalis glycosides Theoretically, digitalis toxicity could develop if patients regularly use, or abuse, anthraquinone-containing substances such as aloes. Clinical evidence Chronic diarrhoea caused by the long-term use, or abuse, of stimulant laxatives such as aloes can cause excessive water and potassium loss, which may cause hypokalaemia that could lead to the development of digitalis toxicity. Although this is often mentioned in reviews1,2 there do not appear to be any reports describing clinical cases of this effect. However, for mention of a case of digoxin toxicity and mild hypokalaemia in a patient stabilised on digoxin and furosemide, who started to take a laxative containing rhubarb and liquorice, see Liquorice + Digitalis glycosides, page 274. The risk of development of digitalis toxicity, including cardiac arrhythmias, is increased by hypokalaemia, which can be induced by the excessive use of anthraquinone laxatives. Importance and management this is a theoretical interaction, but it may be prudent to exercise Mechanism Possible pharmacodynamic interaction involving additive loss of potassium and water by anthraquinone-containing substances and potassium-depleting diuretics. Importance and management this is a theoretical interaction, but be aware of the potential for hypokalaemia in patients who are taking potassium-depleting diuretics and who regularly use, or abuse, anthraquinone-containing substances such as aloes. However, note that, if anthraquinone laxatives are used as recommended (at a dose producing a comfortable soft-formed motion), then this interaction is not clinically relevant. See also Senna + Diuretics; Potassium-depleting, page 350, for the effects of anthraquinones on furosemide absorption. An evaluation of the biological and toxicological properties of Aloe barbadensis (Miller), Aloe Vera. Aloes 29 Aloes + Herbal medicines; Liquorice Consider Liquorice + Laxatives, page 275, for the potential additive effects of anthraquinone-containing laxatives and liquorice. Aloes + Quinidine Consider Senna + Quinidine, page 351 for a potential interaction between anthraquinone-containing laxatives and quinidine. A A Andrographis Andrographis paniculata Nees (Acanthaceae) Synonym(s) and related species Bhunimba, Green chiretta, Kalmegh. Constituents the whole plant contains diterpene lactone glycosides, collectively termed andrographolides, which are based on the aglycone andrographolide and its derivatives, such as neoandrographolide, deoxyandrographolide, andrographiside, andropaniside and others. Interactions overview Andrographis may have antidiabetic and antihypertensive effects, and limited evidence suggests that it may interact with conventional drugs with these properties. Andrographis may also have antiplatelet effects, and so it may interact with conventional antiplatelet drugs and anticoagulants, although evidence is sparse. Jarukamjorn K, Don-in K, Makejaruskul C, Laha T, Daodee S, Pearaksa P, Sripanidkulchai B. Impact of Andrographis paniculata crude extract on mouse hepatic cytochrome P450 enzymes. Use and indications Used in Ayurvedic medicine particularly for jaundice as a general liver and digestive system tonic, and as an immune system stimulant for treatment and prevention of infections. It is also used as an anti-inflammatory and antimalarial, and for cardiovascular disorders and diabetes. When used for the common cold, it is commonly combined with Eleutherococcus senticosus (Siberian ginseng), page 219, or echinacea, page 167. Experimental evidence Kan Jang (a standardised fixed combination of extracts from Andrographis paniculata and Eleutherococcus senticosus (Siberian ginseng), page 219) caused a modest increase in warfarin exposure, but did not alter the effect of warfarin on prothrombin time, in a study in rats. One group of animals was given an aqueous solution of Kan Jang orally for 5 days, at a dose of 17 mg/kg daily of the active principle andrographolide (a dose about 17-fold higher than that recommended for humans). Sixty minutes after the final daily dose of Kan Jang or water, an aqueous solution of warfarin was given orally, at a dose of 2 mg/kg. This may increase the risk or severity of bleeding if over-anticoagulation with warfarin occurs. Importance and management A very high dose of andrographis does not appear to directly affect prothrombin time, but may modestly increase warfarin exposure. As this study suggested that the pharmacodynamic effects of warfarin were not altered, any pharmacokinetic interaction would not be expected to be clinically relevant. However, if the antiplatelet effects of andrographis are confirmed to be clinically important, then an increased risk of bleeding would be anticipated in patients also taking warfarin, as occurs with low-dose aspirin. Therefore, until more is known, some caution is appropriate if andrographis is given in high doses for a long period of time with any anticoagulant. The effect of Kan Jang extract on the pharmacokinetics and pharmacodynamics of warfarin in rats. However, if a patient taking antidiabetic drugs wants to take andrographis it may be prudent to discuss these potential additive effects, and advise an increase in blood-glucose monitoring should an interaction be suspected. Antihyperglycemic effect of andrographolide in streptozotocin-induced diabetic rats. Anti-diabetic potentials of Momordica charantia and Andrographis paniculata and their effects on estrous cyclicity of alloxan-induced diabetic rats. A Andrographis + Antihypertensives Limited evidence suggests that andrographis may have hypotensive properties that may be additive if given with conventional antihypertensives. Clinical evidence Anecdotal evidence suggests that some patients have experienced hypotensive effects while taking andrographis. Andrographis may have antihypertensive effects, and a slight additive reduction in blood pressure is possible if it is given with conventional antihypertensives. Importance and management these experimental studies provide limited evidence of the possible hypotensive properties of andrographis. Because of the nature of the evidence, applying these results to a general clinical setting is difficult and, until more is known, it would be unwise to advise anything other than general caution. Yoopan N, Thisoda P, Rangkadilok N, Sahasitiwat S, Pholphana N, Ruchirawat S, Satayavivad J. Cardiovascular effects of 14-deoxy-11,12-didehydroandrographolide and Andrographis paniculata extracts. Mechanisms of cardiovascular activity of Andrographis paniculata in the anaesthetized rat. Andrographis + Antidiabetics the interaction between andrographis and antidiabetics is based on experimental evidence only. Experimental evidence Andrographolide1 and an andrographis decoction2 lowered bloodglucose levels in animal models of diabetes.
How does the protein control the reduction potential of the iron center in cytochrome c Factors that appear to play a role include the nature of the axial ligands symptoms zika virus buy rumalaya 60pills on-line, the stability and solvent accessibility of the heme crevice symptoms quad strain buy rumalaya 60 pills free shipping, and the hydrophobicities of the amino acids that line the heme crevice symptoms 7 days past ovulation discount rumalaya 60pills line. These issues have been addressed theoretically 142 medication 3 checks rumalaya 60 pills discount,143 and experimentally 144-149 using cytochrome c variants engineered by protein semisynthesis or site-directed mutagenesis symptoms 4 months pregnant generic 60pills rumalaya with visa. Point mutations at either of positions 78 or 83 do not significantly alter E 0 1; however medications you can give dogs purchase rumalaya 60pills on-line, the double mutant (Thr-78 ~ Asn-78; Tyr-83 ~ Phe-83) exhibits a substantially lower redox potential. Evidently, the results of such changes are not necessarily additive; great care must be taken in drawing conclusions about structure-function relations in engineered proteins. Despite the indication from the x-ray structures that only ~ 1 percent of the heme surface is solvent-exposed, the asymmetric distribution of surface charges, particularly a highly conserved ring of Lys residues surrounding the exposed edge of the heme crevice, led to the suggestion that electron-transfer reactions of cytochrome c (and other Class I cytochromes as well) occur via the exposed heme edge. Chemical modification of the surface Lys residues of cytochrome c has afforded opportunities to alter the properties of the surface E-amino groups suspected to be involved in precursor complex formation. These experiments have shown that cytochrome c interacts with inorganic redox partners near the exposed heme edge. Numerous studies 129,152,153 of cytochrome c with physiological reaction partners are in accord with electrostatic interactions featured in the model cytochrome c/cytochrome b5 complex discussed earlier. Similar types of interactions have been proposed for cytochrome c/flavodoxin 154 and cytochrome c/cytochrome c peroxidase complexes. However, the domains on cytochrome c for interaction with physiological redox partners are not identical, as Figure 6. Reactions between cytochrome c and its physiological redox partners at low ionic strength generally are very fast, ~ 10 8 M -I S 1, even though the thermodynamic driving force may be as low as 20 mV, as it is for the reduction of 355 22 25 22 39 cytochrome c reductase 39 cytochrome c oxidase 25 22 su Ifite oxidase cytochrome c peroxidase 39~ Figure 6. Such rates are probably at the diffusioncontrolled limit for such protein-protein reactions. For example, there is evidence 159 that a cytochrome c conformational change in the vicinity of the heme edge accompanies the formation of the complex with cytochrome c oxidase. Studies of the influence of geometry changes on activation energies 52,60, 160 are of particular importance in elucidating the mechanisms of protein-protein reactions. Ruthenium-modified cytochrome c Intramolecular electron transfer in cytochrome c has been investigated by attaching photoactive Ru complexes to the protein surface. The protein-bound Ru complexes are luminescent, but the excited states (*Ru 2+) are rather short lived (1":5 100 ns). When direct electron transfer from *Ru 2+ to the heme cannot compete with excited-state decay, electron-transfer quenchers. If, before laser excitation of the Ru site, the heme is reduced, then the Fe2+ to Ru3+ reaction (ket) can be monitored by transient absorption spectroscopy. The k et values for five different modified cytochromes have been reported: (Ru(His33), 2. Calculations that explicitly include the structure of the intervening medium 8186,164-169 have been particularly helpful in developing an understanding of distant electronic couplings. A, the couplings in proteins can be interpreted in terms of pathways comprised of covalent, H-bond, and through-space contacts. Solid lines are covalent bonds; dashed lines are hydrogen bonds; and the dotted line (His-n pathway) is a space jump. Bacterial Photosynthetic Reaction Centers Photosynthetic bacteria produce only one type of reaction center, unlike green plants (which produce two different kinds linked together in series), and are therefore the organisms of choice in photosynthetic electon-transfer research. The iron atom is indicated by the red dot near the cytoplasmic side of the membrane (bottom). In spite of the near two-fold axis of symmetry, electron transfer proceeds along a pathway that is determined by the A branch. Transient flash photolysis experiments indicate that several electron-transfer steps occur in order to translocate the charge across the membrane (Figure 6. Estimated rate constants for the various electron-transfer steps, together with approximate reduction potentials, are displayed in Figure 6. For each step, the forward rate is orders of magnitude faster than the reverse reaction. The rapid rates suggest that attempts to obtain x-ray structures of intermediates (especially the early ones! However, molecular dynamics methods are being explored in computer simulations of the structures of various intermediates. Clayton, Photosynthesis: Physical Mechanisms and Chemical Patterns, Cambridge Univ. The authors thank Deborah Wuttke for invaluable assistance with the preparation of the final draft of the manuscript and for many helpful discussions. We acknowledge the National Science Foundation, the National Institutes of Health, and the Arnold and Mabel Beckman Foundation for support of our work on biological electron-transfer reactions. These proteins include simple soluble electron-transfer agents (the ferredoxins), membrane-bound components of electron-transfer chains, and some of the most complex metalloenzymes, such as nitrogenase, hydrogenase, and xanthine oxidase. In this chapter we first review the chemistry of the Fe-S sites that occur in relatively simple rubredoxins and ferredoxins, and make note of the ubiquity of these sites in other metalloenzymes. We use these relatively simple systems to show the usefulness of spectroscopy and model-system studies for deducing bioinorganic structure and reactivity. We then direct our attention to the hydrogenase and nitrogenase enzyme systems, both of which use transition-metalsulfur clusters to activate and evolve molecular hydrogen. This classification is now recognized as being not generally useful, since both FezSz and Fe4S4 ferredoxins are found in plants,14,15 animals, Z,6,16 and bacteria. Rubredoxins have no acid-labile sulfide, and generally have a single iron in a more or less isolated site. Additionally, the existence of 3Fe centers and of Fe-S sites that contain a second metal. Simple cytochromes and simple iron-sulfide proteins are similar, in that both can undergo one-electron transfer processes that are generally uncoupled from proton-, atom-, or group-transfer processes. Some of these proteins, such as cytochrome C3 from Desulfovibrio with four hemes 17 or ferredoxin from Clostridium pasteurianum with two Fe4S4 centers,6 can transfer more than one electron, because they have multiple copies of a one-electron transfer group. The cytochromes were discovered in 1886 by McMunn,18 and their role in metabolism was discovered in the 1920s by Keilin (Chapter 6). The intense optical absorbance of these heme-containing proteins contributed singularly to their discovery and biochemical characterization. In contrast, the iron-sulfur proteins, although red to red-brown, absorb far more weakly in the visible region than do the cytochromes. Their presence is sometimes obscured by the cytochromes, and their frequent air instability made their initial recognition and isolation more difficult. It was not until the early 1960s that discoveries by several research groups 19 led to the isolation, recognition, and characterization of the ferredoxins. Although cytochromes were discovered first, the ferredoxins are likely to be the older proteins from an evolutionary perspective. In fact, the amino-acid composition in clostridial ferredoxin is close to that found in certain meteorites. For example, sulfite reductase contains a siroheme and an Fe4S4 center,24 which are strongly coupled and involved in the sixelectron reduction of S03 2- to H2S. Although the Fe2S2 sites do not directly participate in substrate reactions, they are essential to the overall functioning of the enzyme system. The Fe2S2 centers in xanthine oxidase play the same simple electron-transfer role as the Fe2S2 ferredoxins play in photosynthesis. Structurally, all the iron-sulfur sites characterized to date are built up of (approximately) tetrahedral iron units (see Figure 7. In rubredoxins the single iron atom is bound in tetrahedral coordination by four thiolate ligands provided by cysteine side chains. In two-iron ferredoxins the Fe2S2 site consists of two tetrahedra doubly bridged through a pair of sulfide ions, i. For each, we will first discuss the physiological role(s) of the particular proteins, then the structural features, followed by the spectroscopic properties and model systems. Rubredoxin: A Single-Fe Tetrathiolate Protein the physiological role of rubredoxins (sometimes abbreviated as Rd) is not always known with certainty. Some rubredoxins, such as that from the aerobe Pseudomonas oleovorans, participate in fatty acid w-hydroxylation, i. Most rubredoxins contain a single Fe atom, which can exist in the ferrous or ferric state. For the rubredoxin from Clostridium pasteurianum,26 the E0 1 value is - 57 mY, which is much more positive than that of ferredoxins from the same organism (see below). The 6-kDa clostridial protein has only 54 amino acids in its polypeptide chain, and has a very low isoelectric point of 2. Rubredoxins as a class show considerable sequence identity, and the larger 2Fe members of the class show evidence, involving internal-sequence homology, that they may have. A protein from Desulfovibrio gigas, called desulforedoxin,30,31 appears to resemble rubredoxins in some respects, but the two Fe atoms in the 7. The sequence Cys-x-y-Cys is a common one in Fe-S proteins, because it allows both cysteine residues to bind to the same metal site or cluster. The g-values are those for partly reduced samples, and represent a magnetically isolated cluster. The range of distances and angles reveals a slightly distorted tetrahedral structure. Prior to the higher-resolution refinement, a synchrotron-radiation x-ray-absorption spectroscopy study of the iron-absorption edge of rubredoxin was reported. The tetrahedral iron sites in rubredoxins offer an interesting glimpse of ligand-field theory in action, and illustrate the use of various physical methods in * X-ray absorption spectroscopy is most commonly (and conveniently) used with the K-edges of transitionmetal ions, such as Fe or Mo. The former consists of features near the absorption edge itself, which are due to transitions of the photoelectron to bound states and also to other, more complex, phenomena. Although the spectra are highly dependent on the nature of the site, they are quite difficult to interpret, and most analyses are based upon simple comparisons with spectra from model compounds. With proper interpretation of the spectra, very accurate interatomic distances. The four sulfur ligands are expected to split the iron 3d orbitals into e and t2 sets, with the e set lower as shown in Figure 7. The small tetrahedral splitting causes the 3d s Fe 3+ ion to have five unpaired electrons, (e)2(t2)3, 6A 1. Consistent with this configuration, the magnetic susceptibility of rubredoxin gives a f. In exact tetrahedral symmetry, a single, low-energy, low-intensity d-d absorption of designation 5E ~ 5T [(e) 3(t2) 3 ~ (e)2(t2)4] is expected for the high-spin ferrous site (Figure 7. Indeed, reduced rubredoxin displays a band in the near-infrared region at 6,250 cm - I that arises as a component of the 5E ~ sT2 transition. These values for the mononuclear Fe 3+ ion stand in sharp contrast to those for other iron-sulfur proteins, which are usually 5 =! For rubredoxin, the high-spin nature of the ferric and ferrous sites are clearly seen in the Mossbauer spectra. In contrast, the high-spin Fe 2+ ion with an additional d electron has a significant asymmetry, and thus displays * But see Reference 45. Fortunately, this condition is met for at least one member of each one-electron redox couple, i. The need to freeze samples prior to observation can lead to artifacts involving the observation of nonphysiological states and processes. Nevertheless, one cannot usually observe real-time kinetics or be certain that one is observing a physiologically relevant state. The splitting of these levels is influenced by the (s) electron density at the nucleus, and by the electric-field gradient that is set up by nearby atoms. These factors affect the isomer shift and the quadrupole splitting of the Mossbauer spectrum, respectively. Information on nuclear hyperfine couplings is also available when experiments are conducted in the presence of an external (usually applied) magnetic field. Fortunately, the nucleus most commonly (and easily) studied by this technique is present in all the proteins discussed in this chapter, although the level of 57Fe (2 percent natural abundance) must be increased by isotopic enrichment to achieve a high-enough signal-to-noise ratio. For spectra containing one type of site, the spectra are relatively straightforward to interpret. For multisite systems deconvolution is required to get data on individual centers. When possible, selective labeling of sites with 57Fe is extremely helpful in the deconvolution process. The isotope shift also distinguishes between Fe 2 + and Fe 3+, although not as dramatically. Although in rubredoxins with a single Fe atom, this observation of magnetic coupling does not reveal any new information, similar magnetic coupling is particularly useful in unraveling the Fe sites in more complex multiiron proteins. The iron drastically affects the relaxation behavior of such protons, causing line-broadening, sometimes so much that the protons become nonobservable. If observed, the protons are shifted far from the values found in diamagnetic proteins by combinations of Fermi contact (through overlap/through bond) and pseudo-contact (through space/dipolar) coupling. In rubredoxin, 57,57a the Fe-S stretching vibrations are located between 300-400 cm - 1. Deviations of the expected two-band tetrahedral pattern (T 2 and Al modes) are attributable to coupling of the Fe-S vibrations with S-C-C bending modes. This coupling makes for greater variability, and the detailed vibrational assignment is thus more difficult for bands involving the cysteinyl sulfur atoms.
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