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By: Z. Sulfock, M.B. B.CH. B.A.O., M.B.B.Ch., Ph.D.

Professor, Southern Illinois University School of Medicine

Patients can apparently tolerate adverse interactions remarkably well blood pressure chart hong kong order cheap norvasc on-line, and many interactions can be accommodated for (for example hypertension causes and treatment buy generic norvasc, through natural dose titration) blood pressure levels women discount norvasc 10 mg with amex, so that the effects may not consciously be recognised as the result of an interaction blood pressure side effects purchase norvasc in united states online. One of the reasons that it is often difficult to detect an interaction is that, as already mentioned, patient variability is considerable. We now know many of the predisposing and protective factors that determine whether or not an interaction occurs but in practice it is still very difficult to predict what will happen when an individual patient is given two potentially interacting medicines. This effect is compounded when considering the interactions of herbal medicines because they themselves are subject to a degree of variability. Variability of herbal medicines Botanical extracts differ from conventional medicines in that they are complicated mixtures of many bioactive compounds. This makes it difficult to assess the contribution of each constituent to the activity of the whole, and this includes evaluating their possible interactions with drugs. Natural products are also liable to a great deal of variation and, even when standardised to one of more of their constituents, there can still be differences in the numerous other compounds present, and different constituents will affect different metabolic enzymes. As well as the source material, the method by which an extract is made will also affect its composition, and thus its interaction potential. These brief examples start to illustrate that the mechanisms of drug interactions with herbal medicines bear a great relationship to those of conventional drugs. Cytochrome P450 inhibitory action of Echinacea preparations differs widely and co-varies with alkylamide content. Kishida T, Nagamoto M, Ohtsu Y, Watakabe M, Ohshima D, Nashiki K, Mizushige T, Izumi T, Obata A, Ebihara K. For convenience, the mechanisms of interactions can be subdivided into those that involve the pharmacokinetics of a drug, and those that are pharmacodynamic. Although all these mechanisms are undoubtedly relevant to interactions with herbal medicines, this discussion will mainly focus on cytochrome P450 and drug transporter proteins. Cytochrome P450 isoenzymes Although a few drugs are cleared from the body simply by being excreted unchanged in the urine, most are chemically altered within the body to less lipid-soluble compounds, which are more easily excreted by the kidneys. If this were not so, many drugs would persist in the body and continue to exert their effects for a long time. Some drug metabolism goes on in the serum, the kidneys, the skin and the intestines, but the greatest proportion is carried out by enzymes that are found in the liver, mainly cytochrome P450. Cytochrome P450 is not a single entity, but is in fact a very large family of related isoenzymes, about 30 of which have been found in human liver tissue. However, in practice, only a few specific subfamilies seem to be responsible for most (about 90%) of the metabolism of the commonly used drugs. Mechanisms of drug interactions Some drugs interact together in totally unique ways, but, as the many examples in this publication amply illustrate, there are certain mechanisms of interaction that are encountered time and time again. Some of these common mechanisms are discussed here in greater detail than space will allow in the individual monographs, so that only the briefest reference need be made there. This discussion is restricted to those mechanisms that have been extensively investigated with herbal medicines. Note inhibition also reported) Ginkgo (in vitro studies supported by clinical data, but any effect modest. Note induction also reported) Feverfew (in vitro evidence only) Garlic (effects in vitro are probably not clinically relevant) Ginkgo (in vitro studies supported by clinical data, but any effect modest. Note induction also reported) Ginseng (ginsenoside constituents studied; in vitro effects are probably not clinically relevant) Goldenseal (in vitro studies suggest potent effects, but studies in humans suggest only modest clinical effects) Grapefruit (juice has moderate clinical effects; not known if supplements interact similarly) Milk thistle (in vitro studies supported by some clinical data, but any effect modest) Pepper (in vitro piperine (a constituent) has some effect, but ethanolic extracts of the fruit had no clinically significant effects) Resveratrol (in vitro studies suggest modest effects) Rhodiola (in vitro effects with a root extract) Azoles (Itraconazole, Voriconazole) Benzodiazepines and related drugs (Alprazolam, Triazolam, Midazolam; Buspirone, Zolpidem, Zopiclone) Calcium-channel blockers (Diltiazem, Felodipine, Lercanidipine) Corticosteroids (Budesonide, Dexamethasone, Fluticasone, Hydrocortisone, Methylprednisolone) Dopamine agonists (Bromocriptine, Cabergoline) Hormones (Hormonal contraceptives, Oestrogens, Progestogens) Immunosuppressants (Ciclosporin, Sirolimus, Tacrolimus) Opioids (Alfentanil, Buprenorphine, Fentanyl, Methadone) Phosphodiesterase type-5 inhibitors (Sildenafil, Tadalafil, Vardenafil) Protease inhibitors (Amprenavir, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir) Statins (Atorvastatin, Lovastatin, Simvastatin) Saw palmetto (effects in vitro are not clinically relevant) Miscellaneous (Aprepitant, Bosentan, Turmeric (curcumin constituent studied; in vitro Carbamazepine, Cilostazol, Cisapride, Delavirdine, effects are potent) Dutasteride, Eplerenone, Maraviroc, Reboxetine, Rifabutin, Sibutramine, Solifenacin, Tolterodine) * shown to be clinically relevant in drug­drug interaction studies Note that in vitro effects are not necessarily replicated in vivo; findings in vivo often appear weaker than those in vitro. General considerations 9 (a) Enzyme induction Some herbal medicines can have a marked effect on the extent of first-pass metabolism of conventional drugs by inducing the cytochrome P450 isoenzymes in the gut wall or in the liver. A number of herbs have been studied specifically for their effects on these isoenzymes. Those that appear to cause clinically relevant induction of specific isoenzymes are grouped in a series of tables, along with the conventional drugs that are substrates for this isoenzyme. The extent of the enzyme induction depends on the herbal medicine, its dosage, and even the specific extract used (see Variability of herbal medicines, page 6).

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A similar association between nicotine dependence and other substance use disorders has been observed in data from the National Comorbidity Study (349) normal blood pressure chart uk order norvasc overnight delivery. In addition heart attack enrique order 2.5 mg norvasc with mastercard, the presence of alcohol or illicit drug use may be a negative predictor of smoking cessation treatment outcomes (698 heart attack feat mike mccready amp money mark buy norvasc 10 mg low price, 872) blood pressure equipment order norvasc paypal. Although substance use and smoking are often concurrent and conditioned effects may be one important factor in determining the high rates of comorbidity and treatment failure, rates of smoking cessation among these individuals can still be substantial (349). In addition, many individuals with a substance use disorder express an interest in smoking cessation. In patients who do not express a current interest in quitting, motivational interventions should be used. There is conflicting evidence about whether concurrent smoking cessation can increase, decrease, or affect at all the risk of relapse to alcohol (38), and it is also unclear whether cessation should be attempted concurrently or after initial abstinence from other substances. The use of alcohol treatment-related Treatment of Patients With Substance Use Disorders 85 Copyright 2010, American Psychiatric Association. In any case, such smoking cessation treatment should be made available in substance use disorder treatment programs. Treatment in the presence of specific co-occurring psychiatric disorders In the presence of a co-occurring psychiatric disorder, smoking cessation may be more difficult (349, 698, 760, 882). Psychiatric patients appear to have more withdrawal symptomatology when they stop smoking (414, 703, 767), probably as a function of their higher levels of nicotine dependence and smoking consumption. Nicotine nasal spray and vapor inhaler systems provide faster delivery of nicotine, which may increase the rewarding effects of their use. However, no specific studies on these systems have been published in psychiatric patients, and the degree of difficulty of using these delivery systems and their side effects may limit their utility in this population (758, 884). Although many psychiatric patients smoke large numbers of cigarettes and inhale cigarette smoke deeply (885), using higher-than-normal doses of nicotine for heavier smokers has not been consistently shown to be more effective (790, 886). However, supplementation of the nicotine patch with ad libitum use of nicotine gum, lozenges, or inhaler appears helpful (887, 888). Initial psychosocial interventions for psychiatric patients may need to include higher intensities of behavioral therapy, because briefer psychosocial treatments are often unsuccessful (414, 702­704). There has been little study of behavioral therapies for smoking cessation in chronic psychiatric patients, although preliminary studies provide modest evidence that higher-intensity therapies may improve outcomes (701, 703). These studies have typically lacked a treatment as usual or minimal intervention controls, necessitating more controlled studies to establish the efficacy of these treatments. In addition, psychiatric patients, including those who abuse or are dependent on substances, are more likely to benefit from behavioral therapy because of their high incidence of psychosocial problems, poor coping skills, and often, history of benefit from such therapy (730). When deciding between individual or group therapy, it is important to consider patient preference, as many psychiatric patients have experience with one or both kinds of psychotherapy. For some patients, both individual and group therapy may be indicated; for example, a specific problem that undermines cessation. Patients with low levels of coping skills or supports might also benefit from both individual and group behavioral therapy. The motivation to address smoking is often poor in these patients (882, 890), and thus motivational interventions as initial treatments are strongly suggested (891). In addition, the very low quit rates observed for these patients (349) suggest that more intense interventions are needed. Concurrent alcohol and drug abuse in individuals with schizophrenia is high and can complicate cessation efforts; most studies have attempted cessation in patients whose drug use is in recovery and whose psychiatric symptoms are stable. There is some evidence that in smokers with schizophrenia, the use of second-generation antipsychotic agents can either reduce smoking. Similarly, about 17% of nicotine-dependent individuals have a 12-month prevalence of major depressive disorder (347), and 40% of smokers seeking treatment have a history of depression (760, 781). Current (765, 892, 893) and perhaps past (894) depression appears to be a negative predictor of treatment outcome during smoking cessation. Although pharmacotherapies for smoking cessation have not been carefully tested in patients with current (458) or past (456) major depression, antidepressants such as bupropion (158) or nortriptyline (456) should be strongly considered. After a patient has quit smoking, his or her plasma levels of some antidepressants. Comorbid general medical disorders a) General issues Nicotine dependence is the most frequent substance use disorder in all medical settings. Surgeon General (897) concluded that there is sufficient evidence to infer a causal relation between smoking and many medical conditions, including cancer and cardiovascular and respiratory diseases. Despite improved public awareness of its dangers, tobacco use continues to be the leading preventable cause of disease and death in the United States, leading to approximately 440,000 deaths per year (898).

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Clinical evidence A study in 14 healthy subjects found that Kwai garlic tablets 600 mg twice daily for 14 days did not affect the pharmacokinetics of a single 30-mg dose of dextromethorphan blood pressure medication knee pain buy norvasc 10 mg overnight delivery. Importance and management There appear to be two clinical studies investigating the potential for an interaction between garlic and dextromethorphan arrhythmia babys heartbeat purchase online norvasc, both of which found that the pharmacokinetics of dextromethorphan were unaffected by garlic and its constituents arrhythmia symptoms in children cheap norvasc 5 mg without a prescription. Therefore the dosage of dextromethorphan would not need adjusting if patients also wish to take garlic supplements blood pressure quiz pdf order norvasc 10 mg otc. G Garlic + Chlorzoxazone the metabolism of chlorzoxazone is modestly inhibited by garlic but this effect is probably not clinically relevant. Clinical evidence Garlic oil 500 mg, given to 12 healthy subjects three times daily for 28 days, reduced the conversion of a single 500-mg dose of chlorzoxazone to 6-hydroxychlorzoxazone by about 40%. Importance and management There appear to be several clinical studies into the potential for an interaction between garlic and chlorzoxazone. Although these studies suggest that metabolism of chlorzoxazone is modestly Garlic 201 Garlic + Docetaxel Garlic does not appear to affect the pharmacokinetics of intravenous docetaxel. Clinical evidence In a pharmacokinetic study, 10 patients with metastatic, or incurable localised, breast cancer were given 1-hour intravenous infusions of docetaxel 30 mg/m2 weekly for 3 weeks (days 1, 8 and 15). Five days after the first infusion, garlic tablets 600 mg were taken twice daily for 13 days (days 5 to 17). The garlic tablets used were GarliPure Maximum Allicin Formula, Natrol, containing 3. Patients were also given a premedication regimen of oral dexamethasone 8 mg 12 hours before each docetaxel infusion and then every 12 hours for two more doses, and ondansetron 8 mg, ranitidine 150 mg and diphenhydramine 25 mg half an hour before each infusion of docetaxel. Garlic tablets had no effect on the pharmacokinetics of docetaxel on the second or third week, when compared with the first week. This study suggests that garlic is unlikely to alter the activity of this isoenzyme. Therefore what is known suggests that no pharmacokinetic interaction would be expected in patients taking garlic supplements with intravenous docetaxel. Evidence, mechanism, importance and management Aged garlic extract or garlic powder extract did not affect the in vitro antibacterial activity of gentamicin 2. However, no clinically significant interaction is expected as far as antibacterial activity is concerned. Aged garlic extract, garlic powder extract, S-allylcysteine, diallyl sulfide and diallyl disulfide do not interfere with the antibiotic activity of gentamicin. Garlic + Herbal medicines; Caffeinecontaining Garlic did not interact with caffeine, page 200, and is therefore unlikely to interact with caffeine-containing herbs, as a result of this constituent. Garlic + Herbal medicines; Fish oil Garlic supplements and fish oils may have beneficial effects on blood lipids. Clinical evidence In a placebo-controlled study in 46 subjects with moderate, untreated hypercholesterolaemia, combined use of garlic pills 300 mg three times daily (Kwai) and fish oil capsules 4 g three times daily for 12 weeks was compared with either garlic or fish oil alone. Garlic modestly reduced total cholesterol, and fish oil did not alter this effect. Garlic alone reduced low-density-lipoprotein cholesterol, and combined use with fish oil reversed the increase of low-densitylipoprotein cholesterol seen with fish oil alone and produced a reduction similar to that seen with garlic alone. Experimental evidence Garlic oil has been found to enhance the antioxidant effects of fish oils in rats. Importance and management the available clinical evidence appears to come from one study, which suggests that the combined use of garlic supplements and fish oils may have beneficial effects on blood lipids, which are known to be risk factors in coronary artery disease and atherosclerosis. While the clinical importance is inconclusive, any interaction is not expected to be harmful as far as blood lipids are concerned. Effect of garlic and fish-oil supplementation on serum lipid and lipoprotein concentrations in hypercholesterolemic men. The combined effects of garlic oil and fish oil on the hepatic antioxidant and drug-metabolizing enzymes of rats. G Garlic + Food the information regarding the use of garlic with food is based on experimental evidence only.

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Humans are some 3000 times larger and live 20­30 times longer than mice hypertension 2015 buy line norvasc, so if the probability of a cell becoming cancerous was the same per unit time in us as in mice blood pressure while pregnant discount norvasc 10mg without a prescription, none of us would make it out of the womb alive hypertension htn buy norvasc 5 mg with amex, let alone reach puberty (Peto et al blood pressure chart download excel order 2.5 mg norvasc with amex. Selection to prevent cancer must have been ever-present in the evolution of animal development (Graham 1992). Anticancer adaptations must work by attacking the evolutionary process of somatic mutation and cell-lineage selection, and there are 3 ways to do this (Leroi et al. Second, anticancer adaptations can reduce the selective advantage (at the level of competing cell lineages) of 422 Selfish Cell Lineages each intermediary step toward tumor formation, so the mutations do not accumulate as much, or as fast. This can occur by modifiers evolving that make the cancer-contributing mutations more recessive. Cairns (1975) suggests that interposing a series of transiently amplifying cells between stem cells and terminally differentiated cells reduces the number of stem cells required and so also reduces the frequency of cancer (assuming that only stem cells can become cancerous; see also Frank et al. Similarly, having separate patches of stem cells, between which migration is difficult or impossible (as is likely for those in the colonic crypts), also reduces the selective advantage of an oncogenic mutation. Finally, anticancer adaptations can work by adding another set of controls on cell proliferation, so more mutations are required to turn a cell cancerous (Nunney 1999). Cells in the retina (a relatively small and nonproliferative tissue) can become cancerous by the inactivation of only 1 tumorsuppressor locus, whereas cells in the lower gastrointestinal tract (a large, constantly proliferating tissue) require knockouts of 3 loci as well as the activation of an oncogene (Vogelstein and Kinzler 1993). It appears that we have evolved added redundancy in those tissues most requiring it. As we have indicated, it can mean that a defective mutant cell is replaced by a nonmutant neighbor. Most impressive of all, vertebrates have evolved an adaptive immune system that is fundamentally based upon the principle of cell lineage selection (Alberts et al. Briefly, there are about 2 Ч 1012 lymphocytes (B cells and T cells) in the human body (together weighing about the same as the brain or liver). They mostly differ one from another due to rearrangements of the antibody- or T cell receptor-encoding genes. First, lymphocytes that recognize "self " are preferentially killed, inactivated, or induced to change. In this way our immune system can mount a response to almost any foreign antigen and produce antibodies with increasingly higher affinity as an infection persists, while not attacking our own bodies. Cell Lineage Selection in the Germline Though novel genotypes may evolve by cell lineage selection during the lifetime of an organism, those genotypes almost always disappear when the organism dies. There is one wonderfully bizarre exception of a cancer that does not die with its host and is now circulating among feral dog populations (Box 11. The other, more general, exception is for cell lineage selection that occurs within the germline-the precise genotype may be lost by recombination, but changes in allele frequencies can be passed on to subsequent generations. Selection in the germline has been experimentally demonstrated in classic experiments on Drosophila (Abrahamson et al. These experiments involve irradiating males and then measuring the frequency of recessive lethal mutations transmitted by those males on their X chromosome and on one of their autosomes. If one looks at progeny from matings immediately after the irradiation, when there has been no opportunity for any selection, the ratio of lethals transmitted on the X and on the autosome is about 0. But if one looks at progeny from matings 17­21 days after the irradiation, the relative frequency of X-linked lethals is only 0. The sperm cells transferred in these matings would have been derived from cells that were primary spermatogonia at the time of irradiation. These form a small population of asynchronously dividing cells that function as a reservoir for the secondary cells, which undergo 4 synchronous mitotic divisions to produce a cyst of 16 cells, each of which then undergoes meiosis to form a total of 64 haploid sperm. In the development of primary spermatogonia into sperm, selection is expected to act more intensely against X-linked mutations because there is only a single copy of the X, whereas mutations on the autosomes are masked by the other copy. Cell lineage selection in the germline has also been observed in mosaic flies generated by inducing mitotic recombination at particular mutant loci (Extavour and Garcнa-Bellido 2001). Even the most aggressive and invasive cancer cells usually die when their host dies. Once on a new host, the cells reproduce to form a tumor-like growth, usually around the genitals, and the cell lineage can then be transmitted to another host (Plate 9). There are no obvious differences in susceptibility among breeds of dogs, and the cells can also be transmitted to foxes.

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