By H. Sobota. Keene State College.

Other forms of periodontal destruction have been noted with the 55 reduction of vitamin C intake buy zyloprim online pills. Initial studies on vitamin C deficiency in Guinea pigs were carried out by Glickman generic 100mg zyloprim with amex, (1948) purchase discount zyloprim online. Histology revealed that animals on a vitamin C deficient diet for 30 days developed deeper probing depths order cheapest zyloprim, edema and hemorrhage in the periodontal tissues. Lack of Vitamin C was proposed to cause a reduction in connective tissue, inflammatory cells, and inhibit fibroblast proliferation. A study conducted by Waerhaug, (1958) on vitamin C-deficient monkeys demonstrated increased osteoclastic activity leading to increased alveolar bone resorption. Studies showing positive associations with nutritional deficiencies and periodontal disease Author Study Type Nutrient Deficiency Results Glickman et al. Animal; Guinea Vitamin C (none-30 days) Increased periodontal 1948 Pig inflammation and destruction Vogel et al. Cross sectional, 35 Vitamin C (4 day diet analysis) Periodontitis patients had 1979 periodontitis significantly lower vit. Animals; Rats Calcium deficient Osteoporotic alveolar 1969 bone changes and reduction in periodontal ligament fibers Nishida et al. A four day diet analysis was conducted on a small sample of 35 patients (19 females 16 males) between 22 to 59 years old and presenting with generalized moderate to severe periodontitis. They calculated the amount of calories carbohydrates, fat, protein, sodium, calcium, phosphorus, thiamine, niacin, folic acid, fluoride, cholesterol, vitamins A, C, E, and B12 consumed by periodontitis subjects and compared these with 1,222 individuals of the general population without periodontitis. Results demonstrated significantly lower levels of riboflavin and vitamin C consumption by the periodontitis subjects compared to the general population but levels were above the recommended daily allowance. Interestingly, a large percentage of periodontitis subjects showed deficiency in calcium, magnesium, iron, vitamin E and folic acid. This study also found that intake of ascorbic acid in amounts larger than those recommended by the dietary standards does not seem to be associated with better periodontal health. Analysis of over 12,000 subjects using a 24-hour dietary recall but without information on supplement use was conducted to determine the effect of low vitamin C on periodontitis risk. Studies evaluating the role of vitamin C on periodontal status appear to indicate that a weak, but statistically significant effect may be present. In contrast, studies evaluating the effects of vitamin C supplementation on the response to periodontal therapy have largely failed to show any preventable benefit or strong association between such supplements and clinically relevant improvements in therapeutic results. The role of Vitamin C in protection from periodontitis may be related to antioxidant properties which can neutralize free radicals associated with increased oxidative stress in periodontitis subjects. Vitamin C has also been shown to suppress macrophage production of free radicals and is a primary cofactor in collagen synthesis as seen with scorbutic gingivitis an ulcerative condition of the gingival tissues under conditions of severe vitamin C deficiency (Fain et al. Although studies have not shown a clear relation between plasma ascorbate levels and inflammatory periodontitis, this epidemiologic evidence of vitamin C intake and periodontal disease, especially among smokers, may be of significance and warrant further prospective randomized controlled trials. Although oral manifestations are usually confined to the tongue (glossitis), Dreizen et al. The results showed that the animals developed a syndrome similar to pellagra as well as stomatitis. The stomatitis also produced a necrotizing gingivitis and periodontitis and an ulcerative and atrophic glossitis. Intuitively, more longitudinal studies are necessary to demonstrate prolonged affects of B-complex vitamins on gingival and periodontal health. Calcium and vitamin D deficiencies have been evaluated with respect to effects on the periodontal disease. Initial animal experiments involving rats found a reduction in the amount of periodontal ligament fibers along with reduction in alveolar bone density when animals where fed a diet deficient of calcium and vitamin D (Oliver et al. A longitudinal study demonstrated decreased tooth loss in subjects receiving supplemental calcium and vitamin D over 5 years (Krall et al. However 59 supplemental calcium did not have any effect on periodontal indices in patients with untreated periodontal disease (Uhrbom et al. The results of these studies seem to suggest that low dietary intake of calcium may result in increased risk for periodontal disease but that the effects of taking dietary supplemental calcium on arresting periodontal disease or as adjunctive aid in its treatment have not been thoroughly evaluated. The causes of this hyperinflammatory state are multifactorial and at present not fully understood. It is possible that dietary constituents or deficiencies may alter the hyperinflammatory phenotype causing a shift in the balance towards a proinflammatory or anti-inflammatory response. Not only are these free radicals released into the phagosome, but are also emitted into the extracellular matrix. It has been demonstrated that adult periodontitis patients generate higher levels of superoxide in their gingival fluid than healthy controls (Guarnieri et al. Antioxidants are molecules designed to limit oxidation reactions which transfer electrons to an oxidizing agent. Antioxidants interact with each other and with other metabolites either independently or synergistically (Knight et al. It is therefore 61 difficult to ascertain the exact role of individual antioxidants as each may depend on the function of other members of the group. This leads to controversy when trying to determine the effects of depletion of individual antioxidants on periodontal inflammation. Most research has therefore focused on the relationship of periodontal disease and total plasma antioxidant concentrations. Well known antioxidants include vitamin C, vitamin E (tocopherol), carotenoids, and reduced glutathione. Vitamin C is a powerful scavenger of free radicals and protects against oxidants in cigarette smoke (Chapple et al. Vitamin E stops the free radical reactions and stabilizes membranes but due to limited mobility, it may have reduced antioxidant ability. Studies have found that vitamin E may reduce periodontal disease and associated breakdown of collagen fibers (Ritchie & Kinane, 2003, Battino et al. People consuming diets rich in carotenoids from natural foods, such as fruits and vegetables, have been shown to have lower mortality rates and suffer less chronic disease (Diplock, 1998). Recent evidence suggests that defects in polymorphonuclear leukocyte enzymes involved in oxidative burst are to blame for the syndrome (Noack et 62 al. They have been shown to increase antioxidants and reduce bone resorption activity (Schubert et al. These resolvins and protectins stimulate resolution of inflammation by preventing neutrophil penetration, phagocytosing dead neutrophils, enhancing clearance of inflammation and promoting cellular regeneration (Van Dyke et al. Another study examined the effect of a botanical formulation, which included rose hips, a blueberry and blackberry mixture, and a grapevine extract (Kornman et al. The resultant oxidative stress over time may result in chronic systemic inflammation. When glucose and fatty acids are chronically elevated the Krebs cycle and electron transport chain become overloaded. The combination of obesity mediated systemic inflammation and a decrease in antioxidant rich diet could further exacerbate the systemic inflammatory state. The oxidative stress and hyperinflammatory condition associated with these two risk factors may further predispose patients to increased risk of periodontitis by causing an exaggerated response to periodontal pathogens. Model linking nutrition, obesity, systemic inflammation and periodontitis Figure 4 depicts the potential deleterious effects of periodontal disease on systemic inflammation and oxidative stress. The immune responses elicited from exposure to periodontal pathogens have been well established (Gunsolley et al. Periodontal disease has been linked to numerous inflammatory conditions, such as diabetes (Genco et al. The inflammatory burden caused by chronic periodontal disease is postulated to be one of the reasons leading to associations with systemic diseases. The high prevalence of immune responses in children reported in the initial portion of document is cause for concern. Periodontitis may be exacerbated by the increase in systemic inflammatory burden caused by either of these two maladies. The dentist is in a prime location to counsel on risk factors for periodontitis which include educating patients on maintaining appropriate weight and encouraging a balanced nutritious diet. Reduction in both of these modifiable risk factors may have a beneficial effect not only on the patient’s periodontal health but on systemic health as well. Poor nutritional habits, which are usually established in childhood, have the potential to further exacerbate systemic inflammation and oxidative stress. The long term exposure of this inflammatory burden, coupled with increased immune responses to periodontal pathogens in young children, as reported in the observational study at the beginning of this document, may further compound the issue.

As with in vitro studies buy 300mg zyloprim visa, in vivo studies can often use a screening approach involving probe drugs discount 300mg zyloprim. Where interactions are found buy zyloprim 300mg visa, the studies of probe drugs and other drugs will provide a basis for specific recommendations on product labeling as to what An Integrated Approach to Assessing Drug-Drug Interactions 671 concomitant uses should be avoided or what dosage adjustments to make purchase zyloprim 300mg line. A critical determination for substrate effects is the size of the effect, measured in the in vivo interaction study, and the importance of the effect. Thus, a 50% increase in blood levels of a well-tolerated drug with little dose-related toxicity may require no dosage adjustment. The same degree of increase for a drug with a narrow therapeutic range might require careful adjustment in dose or avoidance of coadministration. The issues in the areas of study design and data analysis are discussed in more detail in the following section. If in vitro studies and other information suggest a need for in vivo meta- bolic drug-drug interaction studies, the following general issues and approaches should be considered. Depending on the study objectives, the substrate and interacting drug may be investigational agents or approved products. Study Design In general, interaction studies compare substrate levels with and without the interacting drug. Any may be suitable, depending on the specific objectives of the study and the desired outcome. The study may use a randomized crossover, a one-way (fixed sequence) crossover, or a parallel design. Depending on cir- cumstances, the studies can use various durations of exposure for substrate and interacting drug: single dose/single dose, single dose/multiple dose, multiple dose/single dose, and multiple dose/multiple dose. In general, the inhibiting/inducing drugs and the substrates should be dosed so that the exposure of both drugs is relevant to their clinical use. A substrate drug intended for chronic administration should generally be given until steady state is attained, with assessment of pharmacokinetics over one or more dosing intervals followed by administration of the interacting drug, which is also given until steady-state concentration is reached, again with collection of pharmacokinetic data on the substrate. The studies of erythromycin-terfenadine and ketoconazole-terfenadine interactions in healthy volunteers (14,15) are examples of this one-way, or fixed-sequence, crossover design. If the substrate drug has a long half-life and accumulates, the probability of seeing an effect may be enhanced by giving the substrate drug as a single dose and the interacting drug as multiple doses. Multiple-dose studies would generally be necessary to ensure that relevant metabolites can be assessed and that the relevant dose of the interacting drug is used, but special approaches may also be useful. For example, a loading dose of the potential inhibitor may allow relevant levels to be obtained more rapidly and selection of a one-way (fixed-sequence) crossover or a parallel design, rather than a randomized crossover study design, may also help. Using a one-way crossover design, a recent study (17) showed that multiple-dose administration of sertraline inhibited the clearance of desipramine to a considerably greater extent than did a single-dose administration. Inducers may take several days or longer to exert their effects, while inhibitors generally exert their effects more rapidly. For this reason, a more extended period of exposure to interacting drug may be necessary if induction is to be assessed. The study design should also allow assessment of how long the inhibition or induction effect will last after an interacting drug has been removed from the dosing regimen. This effect can be observed in the randomized crossover design and in the one-sequence or parallel designs by adding an additional period in which the interacting drug is withdrawn. In this case, mibefradil both increased blood levels of the dihydropyridine and inhibited the increased heart rate needed to overcome the lowered blood pressure. For an inhibitor drug that induces its own metabolism, a multiple-dose study design should be used so that the extent of interaction is not over- estimated. This inhibition may be partially explained by the lower exposure to rito- navir after multiple doses than after a single dose. When a pharmacodynamic effect is also being measured, attainment of steady state for the parent or metabolite whose pharmacodynamic effects An Integrated Approach to Assessing Drug-Drug Interactions 673 are being measured is important. In addition, inclusion of a period of the interacting drug alone in the sequence is often advisable so that its contribution to the pharmacodynamic effects can be assessed. Studies can usually be open label (unblinded), unless pharmacodynamic endpoints (e. Study Population Clinical drug-drug interaction studies can generally be performed in healthy volunteers unless safety considerations preclude their participation. Sometimes, use of subjects/patients for whom the substrate drug is intended offers advan- tages, including the opportunity to study pharmacodynamic endpoints not present in healthy subjects. Improved understanding of the metabolic basis of drug-drug interactions allows the use of more informative approaches to choosing substrates and potential interacting drugs. Figure 1 describes a decision-making process (20) for the conduct of in vivo drug interaction studies once a new drug is characterized as a substrate for a particular metabolic pathway or an inhibitor of that pathway. In contrast to earlier approaches that focused mainly on a specific group of approved drugs (e. In studying an investigational drug as the interacting (inhibiting or inducing) drug, the choice of substrates (approved drugs) for initial 674 Huang et al. In testing inhibition, the substrate selected should generally be one whose phar- macokinetics are markedly altered by coadministration of known specific inhibitors of the enzyme systems to assess the impact of the interacting inves- tigational drug. If the initial study shows that an investigation drug either inhibits or induces metabolism, further studies using less sensitive substrates, based on the likelihood of coadministration, may be useful. In testing an inves- tigational drug for the possibility that its metabolism is inhibited or induced (i. The choice of interacting drug can then be based on known, important inhibitors of the pathway under investigation. If the study results are negative, then absence of a clinically important drug-drug interaction for the metabolic path- way would have been demonstrated. If the clinical study of the strong, specific inhibitor/inducer is positive, it should generally be determined in further clinical studies whether there is an interaction between the test drug and less potent specific inhibitors or inducers. Use of the drug with grapefruit juice may call for caution depending on the drug’s exposure-response relationship (23). John’s wort may be listed in the labeling along with other known inducers, such as rifampin, rifabutin, rifapentin, dexamethasone, phenytoin, carbamazepine, or phenobarbital, as possibly decreasing plasma levels. When the above study shows significant interaction, further evaluation with weaker inhibitors may be necessary. In testing an investigational drug for the possibility that it may be an inhibitor/ inducer of P-gp in vivo, digoxin or other known substrates of P-gp should be used. In testing an investigational drug for the possibility that its transport may be inhibited or induced in vivo (as a substrate of P-gp), an inhibitor of P-gp should be studied. In testing an investigational drug for the possibility that its disposition may be inhibited or induced (i. Route of Administration For an investigational agent used as either an interacting drug or substrate, the route of administration should generally be the one being studied in trials. If only oral dosage forms will be marketed, studies with an intravenous formulation are not usually necessary, although information from oral and intravenous dosings may be useful in discerning the relative contributions of alterations in absorption and/or presystemic clearance to the overall effect observed for a drug interaction. For example, the interaction studies of clarithromycin and intravenous or oral doses of midazolam enabled Gorski et al. Sometimes the use of certain routes of administration may reduce the utility of information from a study. Dose Selection For both substrate and interacting drug, testing should maximize the possibility of finding an interaction. Doses smaller than those to be used clinically may be needed for substrates on safety grounds and should provide an adequate assessment of an interaction. The differential effects of different doses of ritonavir on the plasma levels of saquinavir (18) demonstrate the dose effect of an interacting drug. In some cases, these measures may be of interest for the inhibitor or inducer as well, notably where the study is intended to assess possible interactions between both study drugs. In certain instances, an understanding of the relationship between dose, blood levels, and response may lead to a special interest in particular pharmacokinetic measures/parameters. For example, if a clinical outcome is most closely related to peak concentration (e. In certain instances, reliance on endpoints in addition to pharma- cokinetic measures/parameters may be useful. Increasingly, also, these factors can affect the regulatory decision to approve such a drug and/or how it is labeled. Section 505 of the Food Drug and Cosmetic Act requires that, for approval, a drug must be demonstrated to be both effective and safe when used as labeled. Safety is not an absolute measure but rather reflects a conclusion that the drug’s benefits outweigh its risks. Among the risks that must be considered is the presence of individuals who are at particular risk because of individual characteristics (e.

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Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis generic zyloprim 100mg fast delivery. Abnormal hepatic methionine and gluta- thione metabolism in patients with alcoholic hepatitis cheap zyloprim 100 mg visa. Acetaminophen hepatotoxicity: what do we know cheap zyloprim 300 mg with mastercard, what don’t we know purchase zyloprim 100 mg otc, and what do we do next? Acyl glucuronides revisited: Is the glucuronidation process a toxification as well as detoxification mechanism? Metabolic activation of diclofenac by human cytochrome P4503A4: role of 5-hydroxydiclofenac. Roles of human hepatic cytochrome P450s 2C9 and 3A4 in the metabolic activation of diclofenac. Studies on the metabolism of troglitazone to reactive metabolites in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidine ring scission. Drug-protein covalent adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Future of toxicology - metabolic activation and drug design: challenges and opportunities in chemical toxicology. This ever-expanding pharmaceutical arsenal is available to physicians to treat a large number of diseases (both human and veterinary). As the mean age of industrialized nations increases, in part due to advances in medical care, the need to treat multiple disease processes simultaneously increases the probability that large numbers of people will receive concomitant therapy with multiple drugs. Consequently, there is an increased risk of adverse drug-drug interactions as more drugs are used to treat a variety of conditions in the same patient. Identifying the potential for adverse drug-drug interactions is increasingly difficult when patients are cared for by multiple specialists, each primarily concerned with one organ system, without overall coordination of the patient’s management by one person. In many situations, the potential for drug-drug 709 710 Petty and Vega interactions can be minimized by appropriate choices of agents, particularly when options exist with different mechanisms of action, sites of metabolism, and routes of excretion. There are, unfortunately, situations where interactions may not be avoidable and the risks and benefits must be carefully assessed. Thus, drug-drug interactions must be evaluated in light of the therapeutic class and the risk/benefit ratio. This chapter will focus on drug-drug interactions and their effect on the market place. Prescription drug sales (retail pharmacies) in the United States in 1997 totaled $81. Prilosec became the first prescription drug to exceed $5 billion, with worldwide sales in 1998 of $5. The six top-selling drugs in 1997 1 1 1 1 1 (Prilosec, Prozac ,Zocor , Epogen ,Zoloft ,andZantac )eachhadU. Worldwide (North America, Europe, Japan, Latin America, Australia) retail pharmacy sales totaled more than $185 billion in 1998 (3). Among the most significant of these factors are the efficacy and safety of a given drug. Those two factors are the most important considerations in the process by which drugs receive approval from regulatory agencies to allow their marketing. Those factors are also important for drugs after they gain entry to the market, together with additional factors, such as dosing convenience and cost when more than one drug is available to treat the same condition. Perhaps the most common type of interaction is where one drug alters the pharmacokinetics of a second drug. Alteration of pharmacokinetics can include inhibition by one drug of the metabolism of a second drug (e. Conversely, induction of metabolism of one drug by another can also produce untoward effects if plasma levels of the second drug become subtherapeutic. An example of such an interaction was the reported interaction of rifampin with oral contraceptives containing ethinyl estradiol, where concomitant use of rifampin accelerated the metabolism of ethinyl estradiol, resulting in decreased efficacy as contraceptive and unwanted pregnancies (4). Drug-Drug Interactions: Marketing Perspectives 711 Since 1964, *60 drug products have been withdrawn from the U. Most of the compounds withdrawn primarily for safety had toxicities directly attributable to the com- pound. Only two of these drugs (terfenadine and mibefradil) were withdrawn primarily for their high incidence of adverse drug-drug interactions. The dis- cussion that follows will describe the experience with these two drugs and the experience with cimetidine, where drug-drug interactions have had a significant impact on its market position. Terfenadine Terfenadine was introduced into the marketplace as the first nonsedating hista- mine-1 (H1) receptor antagonist. Its patent protection was near expiration when the drug was voluntarily withdrawn from the antihistamine market in 1997. It was thought that the antihistaminic effect of terfenadine was due to direct interaction with the H1 receptor. Subsequent studies revealed that terfenadine was completely metabolized in vivo to fexofenadine, a metabolite entirely responsible for the antihistaminic effect (6). The unique property of fexofenadine compared to first-generation antihistamines (diphen- hydramine, chlorpheniramine) was its inability to cross the blood-brain barrier, thereby avoiding the sedation seen with the first-generation antihistamines. Terfenadine was indicated for use in allergic rhinitis (both seasonal and peren- nial), and the recommended dose was 60 mg twice daily. Clinical Pharmacology Terfenadine is at least 70% absorbed after oral administration but is rapidly metabolized by first-pass metabolism to fexofenadine (terfenadine carboxylate) and an inactive dealkylated product. Fexofenadine is about 70% protein bound and exhibits biphasic elimination with an initial plasma half-life of 3. Fexofenadine is excreted mostly unchanged (80% in feces, 12% in urine), with <10% converted to inactive metabolites (7). Adverse Experiences The first published report of a serious adverse event due to an interaction of terfenadine with another drug was that of a young woman who was taking terfenadine and subsequently began taking ketoconazole. Within a few days after beginning ketoconazole therapy, she experienced syncopal episodes and was found to have torsade de pointes (polymorphic ventricular tachycardia) (11). Torsade de pointes was also seen in patients with liver failure who took terfe- nadine and in patients who simultaneously received erythromycin and terfena- dine (12). On the basis of the initial reports of torsade with terfenadine, a ‘‘Dear Doctor’’ letter was issued by the manufacturer of Seldane in 1990. The occurrence of cardiac toxicity was closely correlated with terfenadine use, and subsequent in vitro studies confirmed that terfenadine (but not fex- ofenadine) efficiently blocks cardiac potassium channels (14). Thus, the direct inhibitory effect of terfenadine on cardiac potassium channels results in prolongation of cardiac repolarization, which is a well-known cause of ventricular arrhythmias. In one death in which terfenadine was implicated, plasma level of the drug was 55 ng/mL several hours after the last ingestion of the drug (when it normally should be undetectable). Market Dynamics Seldane held market exclusivity as a nonsedating antihistamine from its launch 1 in 1985 until 1989, when astemizole (Hismanal ) entered the market. Hismanal Drug-Drug Interactions: Marketing Perspectives 713 did not penetrate significantly into the market because of perceived inferior efficacy (longer onset of action) and cardiac toxicities similar to Seldane (7). On the basis of its nonsedating property, efficacy, and convenient dosing, Seldane maintained market leadership, with a ranking of the fifth most commonly pre- scribed drug in the United States in 1990. In 1991, 17 million prescriptions were issued, and there were more than 100 million users of Seldane worldwide. Despite the black box warning, Seldane had worldwide sales of $700 million in 1994 and held up to 29% market 1 share in the United States in 1995. With the launch of Zyrtec in 1996 (pro- moted as safer and equally effective), market share of Seldane plummeted to 2. When it was recognized that fexofenadine was the active metabolite, efforts were begun to register it as a separate entity. Mibefradil 1 Mibefradil (Posicor ) was launched in the United States in June 1997 by Roche, Switzerland. At the time of launch, it was projected to eventually provide 1–3% of Roche’s sales. Average reductions of diastolic blood pressure of as much as 15 mmHg were seen with the 100-mg dose. Thus, it was indicated for use in hypertension and stable angina at doses of 50 or 100 mg once daily (15). It was reported to be well tolerated, with the most common adverse experiences being head- ache, leg edema, dizziness, and fatigue at incidences similar to those with placebo. Clinical Pharmacology Oral bioavailability of mibefradil is dose dependent and ranges from 37% to over 90% with doses of 10 mg or 160 mg, respectively.

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Because pefloxacin undergoes N-demethylation to norfloxacin (51) and norfloxacin is much more potent as an inhibitor than pefloxacin (50) order 100mg zyloprim overnight delivery, the observed in vivo interaction seen for pefloxacin may cheap 300mg zyloprim otc, in part order generic zyloprim from india, be due to norfloxacin purchase zyloprim 100 mg without prescription. Many other quinolone antibacterial agents have been investigated for their interaction with theophylline, and ciprofloxacin has also been shown to have notable inhibitory effects (52). The potent inhibition of caffeine metab- olism by fluvoxamine results in an approximate fivefold decrease in caffeine clearance and sixfold increase in half-life (56). Caffeine, although not used ther- apeutically, is, given the worldwide consumption of tea, coffee, and other caffeine- containing beverages, of significant interest. The primary route of caffeine metabolism is via N-demethylation to paraxanthine, theophylline, and theobromine. In addition, there is the suggestion that pÀp stacking interactions also occur between some of the substrates and the active site (62). Warfarin is administered as a racemate, with different P450 enzymes being involved in the metabolism of the different enantiomers. In fact, many of these compounds are relatively weak inhibitors of the enzyme, with the exception of fluvastatin. This inhibition was also observed in vivo when diclofenac and fluvastatin were coadministered. In this case, there was an increase in diclofenac Cmax, a reduction in oral clearance, and a decrease in the 4 -hydroxydiclofenac/diclofenac0 urinary ratio (76). This makes the enzyme an important target for drug-drug interactions, but also somewhat less straightforward to investigate clinically, at least if a significant interaction was to be pursued to steady state. Other than warfarin, there are a substantial number of studies using phenytoin and tolbutamide. The use of phenytoin is complicated by virtue of its nonlinear kinetics, long half-life, and narrow therapeutic margin. However, it has been used to confirm the in vitro finding that phenytoin and tolbutamide are metabolized by the same P450 enzyme (79). Tolbutamide Tolbutamide is metabolized by hydroxylation of the methyl tolyl group in man (80), forming hydroxytolbutamide. However, it is the initial hydroxylation that is rate limiting for elimination, accounting for approximately 85% of the clearance in man. This elimination pattern has enabled urinary ratios to be used to assess tolbutamide interactions, which gave a good correlation with total clearance on coadministration with sulfaphenazole (82). Selectivity Substrates for this enzyme include (R)-mephobarbital, moclobemide, proguanil, diazepam, omeprazole, and imipramine, which do not show obvious structural or Human Cytochromes P450 and Metabolism-Based Drug-Drug Interactions 67 physicochemical similarities. In an in vitro study citalopram appeared to be a weak inhibitor (Ki > 50 mM), with the remaining compounds all having Ki values of less than 10 mM (88). However, other substrates for this enzyme, including diazepam and imipramine, have been identified that have the potential to be used as probes (90,91). The (S)-mephenytoin phenotype (genotypically conferred or by administration of an inhibitor) is determined following an oral dose by measuring the ratio of (S)-mephenytoin to (R)-mephenytoin in the 0- to 8-hour urine (93). Imipramine Imipramine is metabolized mainly by N-demethylation and 2-hydroxylation in man. In addition, a much larger study showed that the S/R ratio for mephenytoin correlated with the N-demethylation of imipramine (95). It is the ionic interaction between this protonated nitrogen atom and an aspartic acid residue that governs the binding. The relative strength of this ionic interaction means that the affinity for substrates can be high and that this P450 enzyme tends to have many examples of low Km and low Ki interactions. Once the ionic interaction is formed, any difference in binding affinity could be attributed to other pÀp or hydrophobic interactions. One advantage for in vivo drug-drug interaction studies is that most of the substrates were identified in the clinic rather than by the use of a battery of in vitro methods. Dextromethorphan Dextromethorphan is well tolerated, with few clinically relevant side effects, and it is a readily accessible drug in a large number of countries, making it ideal for drug-drug interaction studies. Metoprolol Metoprolol is a b-blocker that has been proposed as a pharmacokinetic alter- native to debrisoquine in countries where it is difficult to use debrisoquine. The a-hydroxymetoprolol metabolite has been shown to be bimodally distributed and to correlate with the debrisoquine oxidation phenotype (125). These studies would suggest that in some ethnic groups metoprolol may not be a suitable probe. Generally such binding, if based solely on hydrophilic interactions, is relatively weak and without specific interactions, which allows motion of the substrate in the active site. Thus, a single substrate may be able to adopt more than one orientation in the active site, and there can be several products of the reaction. These models suggest the active site pocket to be large and open and made up predominantly of hydrophobic and some neutral residues, together with a small number of polar side chains. The large number of aromatic side residues allows for the possibility of pÀp inter- actions with aromatic substrates. In addition, the presence of polar residues sug- gests the possibility of hydrogen bonds between substrates and the active site. Clearly, the most frequent outcome is a loss of efficacy, which is perhaps less serious than inhibition interactions, although the consequences of coadministering rifampin with the oral contraceptive pill can lead to contraceptive failure (141–143). The drug is basic, partially ionized at physiological pH, and highly lipophilic, and it is also a substrate for the enzyme, being metabolized in the imidazole ring, the site of its ligation to the heme (144). This high-energy interaction results in a high potency of enzyme inhibition, with Ki values typically substantially less than 1 mM. Such compounds are substrates for the enzyme, but metabolism is believed to form products that deactivate the enzyme. Some of these substrates are not ideal targets for investigations of drug-drug interactions, because of potential safety concerns upon inhibition, e. This test shows fairly good correlations with trough cyclosporin concentrations (158) and clearly demonstrates the inductive effect of rifampin (157). The test is still somewhat invasive (intravenous adminis- tration) and does not assess presystemic effects; a further limitation is the need to administer radioactivity. Midazolam clearance has been increased in patients receiving phenytoin (164) and reduced in patients receiving eryth- romycin (165) or itraconazole (166), showing wide utility for drug-drug inter- action studies. Pharmacokinetic studies with nifedipine clearly identify inhibitors, such as itraconazole (169) and grapefruit juice (170), and inducers, such as the barbiturates (171) and rifampin (172). Clearly, other 74 Clarke and Jones metabolic pathways or mechanisms of clearance are also contributing to bupropion clearance in vivo. This enzyme has a growing list of structurally diverse substrates, including some major therapeutic agents such as the glitazones, repaglinide, paclitaxel, and cerivastatin, certainly enough to build substrate pharmacophores (184). The interaction of gemfibrozil with cerivastatin (189) led to the withdrawal of this statin from the market. This fully justifies the intensive research in this area and the pharmaceutical industry’s focus on such drug-drug interactions. This focus is reinforced in this volume, in which P450 is either the major or the most sig- nificant subject of over half the chapters, and inhibition and induction, in vitro and in vivo, are further exemplified and discussed. The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. Comparative studies of drug- metabolizing enzymes in dog, monkey, and human small intestines, and in Caco-2 cells. Identification of gluticoid-inducible cytochromes P-450 in intestinal mucosa of rats and man. Differentiation of absorption, first-pass gut and hepatic metabolism in man: studies with cyclosporine. Intestinal drug-metabolism and anti-transport processes-a potential paradigm shift in oral-drug delivery. Effects of intestinal and hepaticmetabolism on the bioavailability of tacrolimus in rats. Metabolism of the immunosup- pressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability. Metabolism and transport of the macrolide immunosuppressant sirolimus in the small intestine. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics.

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Work with your doctor, nurse, or diabetes educator to plan how you will manage your diabetes. Work with your health care team to keep your feet, eyes, heart, and teeth healthy. The former are proverbs used for medical purposes even though they may have no medical content. The perception of a proverb as medical in content is flexible, varying from collection to collection. In thematic proverb collections the items are usually taken out of the context but their very inclusion is in itself a context-specifying factor. A new definition of applied folklore is proposed, stressing the role of non-folklorists. The wish to use prov- erbs for concrete purposes inheres in the material itself as much as the wish to reveal its universal formulas. He informed his readers that he was publishing it after becoming disillusioned with the topic, which initially had been designed for his doctoral dissertation (Krikmann 2001: 11). This confession encourages me to open this article, which is intended for publication in this journal’s issue hon- ouring Prof. My interest in medical proverbs began in my early student years, when my father, a physi- cian, suggested this topic to me as a joint venture. For two years we searched for medical proverbs in various collections, discussing the criteria for the no- tion “medical” and for the classification of our material. Concurrently with our joint collecting activities I completed my seminar paper and even published a short paper, which I do not include in my list of publications. At that point I began to harbour misgivings as to the scientific value of the topic, and I took the opportunity to discuss them with two venerable literary scholars, Miron Petrovskii and Vadim Skuratovskii. Their verdict was unanimous: although the collection was interesting and the seminar work showed a student’s ability in research, the topic itself had no philological value. Both the collection and Folklore 46Folklore 46Folklore 46Folklore 46Folklore 46 http://www. Although presented to me very politely and amiably, this conclusion caused me a profound psychological trauma. For six months I could write nothing at all, and then I switched abruptly from folklore to literary studies. My emigra- tion in 1991 caused me to return to the path of folklore studies, but one angle of it, namely medical proverbs, remained previously sealed for me and thus my father must be again mentioned. He carried our collection in his immi- grant luggage; he even brought along my old seminar paper. For thirty years he tried to persuade me to publish our collection, occasionally encountering “explosions” from myself. He refused to publish it under his own name, al- though I ardently suggested that he do so and while I said “never”, he still waited patiently. Then, suddenly, the situation changed when two years ago, in one of our numerous fervent debates on medical proverbs it struck me that my father was growing old. This understanding changed the whole perspective of the issue so I was not about to deprive him of one of the few pleasures remain- ing to him. The fear that he might not see this work published, and I would blame myself for it, was bitterer than the memory of my failure so long ago. And so I agreed to publish the book of medical proverbs, with the proviso that he typed it out himself on the computer and as my father was still not really computer literate the task was enormous. But he accomplished it, and even added many Jewish proverbs himself and so the upshot is that our book has been published. And my paper on medical proverbs can be viewed as one of the confirmations of the wise folk sayings – “Never say never”. But the difference should be defined as not all the proverbs used by medical practitioners are medical in content; and medical content does not automati- cally imply the use of these items in medicine. Medical proverbs and proverbial sayings uttered by people constitute pithy observations, opinions and advices across a whole array of human existence, covering life, death, illnesses, and relations of doctors and patients. Elmquist introduced the notions of indirect and direct references to physiologi- cal matters in proverbs and proverbial sayings, limiting his research to the latter group (Elmquist 1934: 75). In principle, I accept this dichotomy, although Elmquist’s examples of indirect references to physiological matters are, I be- 112 www. I see no physiological significance in such prov- erbs as “A new broom sweeps clean” or “Coming events cast their shadows before” (Elmquist 1934: 75). To my mind, the narrow cluster of medical prov- erbs includes those about illness, pain, doctors, patients, folk healers, healthy and unhealthy habits, medication, and diagnostic and prognostic proverbs, while a broad cluster also encompasses proverbs and sayings about life and death, general ideas about age and so on. To the best of my knowledge, the collections of medical proverbs are not limited to the narrow group, which is as it should be. The borders between health and illness, age and illness, and even life and death, are permeable and cannot be sealed. It has been noted that the prov- erbs’ reflection of the “actual healing art is poor” (Garrison, 1928: 984; Anony- mous 1914: 875) and that they “are not particularly enlightening from the scientific point of view” (Mieder 1993: 153).

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In others it produces a restfulness purchase genuine zyloprim on-line, which results in sleep buy on line zyloprim, independent of further action of the remedy order zyloprim uk. In hysterical attacks quality zyloprim 300 mg, the agent is valuable, as it produces general quiet, and refreshing sleep. It may be used in the place of morphine and opium with those who are addicted to a habit for these drugs, and it will produce the same results. The drug is a treacherous one, and consequently dangerous, and must therefore be given with care. In very minute doses, it is given in bronchitis, where there is a deficiency of secretion, or in croup, producing relaxation and expectoration. It is given as an expectorant in cough mixtures, with good results, but its emetic influence should not be induced. One one-hundredth of a grain, repeated every two hours, will be sufficiently large dosage. It produces a Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 314 watery secretion of mucus, which is often undesirable. It should be used only with adults, as stated, as children are too susceptible to its influence. Kinnett has used it in pain from spasms of the pyloris, and others mention its influence for spasmodic pain in severe, acute stomach disorder in sthenic cases. Dice believes apomorphine given in small doses frequently repeated in the initial stage of appendicitis will prevent the development of many cases of this disease. He dissolves also a dram of sulphate magnesium in four ounces of water and gives a teaspoonful every two hours with it. Apomorphine in doses of One-thirtieth of a grain or less, frequently repeated controls some very severe cases of vomiting. In the treatment of alcoholism, this agent is given in sufficient quantity to produce mild nausea; then one-thirtieth of a grain of strychnine or other indicated stimulant is given for its influence upon the nervous system at the same time. Occurrence—An alkaloid of opium closely related to morphine, often, if not carefully prepared, containing a certain proportion of morphine. Character—White octahedral crystals, bitter, odorless, permanent, soluble in eighty parts of water and in three parts of alcohol. Physiological Action—Its influence is that of an anodyne and antispasmodic, more active as an antispasmodic than morphine and much less narcotic. It controls pain without checking secretion to as great an extent as the other alkaloids of opium. Therapy—It has a more marked influence upon pain in the abdomen and in the pelvic organs. Spasms, neuralgia and other painful conditions in these parts are well controlled by codeine. It has been given in doses of fifteen or twenty grains daily for this purpose, in some cases with permanent results. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 315 Codeine has a marked influence upon spasmodic cough. It is often given to soothe irritable conditions of the air passages and to control persistent annoying and exhausting cough. Opium is stimulant and narcotic, according to the dose and susceptibility of the patient. Infants and old people are easily poisoned by the drug, while those addicted to alcohol can take very large doses without any bad effects; and those accustomed to the drug can take a poisonous dose with impunity. In the healthy adult a moderate dose of opium stimulates all the nervous functions of the body, raises the spirits and excites intellectual action; this gives way to a condition of placidity, freedom from care, and a state of quiet enjoyment. In an hour or less, con-sciousness is lost in sleep, which may continue for eight hours or longer. On waking there is evidence of disturbance of the functions of the organism, such as nausea, vomiting, headache, constipation and diminished secretion, except that of the skin. In a dose sufficient to cause death the period of excitement is short, while the strength of the system rapidly gives way to drowsiness and apoplectic sleep. There is stertorous breathing, dusky countenance, slow pulse, nearly total insensibility, only responding slightly to violent agitation, with confusion of the mind, and an inclination to continue in a comatose state with increasing debility. After a few hours, six to twelve, according to the dose and the resisting power of the patient, the face becomes pale, the pulse from being full and strong becomes weak and thready, with cold extremities, a cool and clammy skin, a slow gasping respiration; a condition from which it is impossible to rouse the patient and death soon follows. The pulse is first slow from stimulation of the vasomotor nerve centers, and becomes rapid as these become paralyzed. The pupil is first contracted by stimulation of the oculo-motor nerves, and dilates as death approaches and these become paralyzed. With some individuals there appears to be an inherent and usually Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 316 permanent idiosyncrasy against the action of opium and morphine. These are nausea or violent vomiting, spasm of the stomach and loss of appetite, obstinate constipation or abdominal pain. In others there is nervous excitement, restlessness, headache, tremors, general distress and an increase of pain. Given under the conditions we have named as contraindications, it will often produce these phenomena; where there is an absence of idiosyncrasy, and where given under the proper conditions, the effects would be desirable. Itching of the skin, inducing an apparent miliary eruption, is one of the unpleasant effects of its use, which, like any one of the others, may be always greatly exaggerated in certain individuals. By using water as a solvent, or combining opium with ipecac or camphor, or in some cases with the bromides, these unpleasant effects can, in great measure, be overcome. It has poisoned infants while nursing, the mother either taking it as medicine or habitually. Caution—All of the effects of these agents are especially marked in infants and early childhood. The nervous system is profoundly impressed by them, and the dose, if given at all to very young babes, should be infinitesimal. Its administration can be avoided in nearly all cases with these little patients, as we have access to many agents which, while not working actively in adults, produce most satisfactorily soothing, anodyne or pain- relieving properties in childhood. Opium addiction is acquired by continued use of the agent, and is debasing and deadly in its effects. Another serious objection to its administration in large doses often is that it conceals or obscures the actual condition, the diagnostic symptoms or the specific disease indications, and permits disease to advance to formidable proportions before its real character is known. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 317 This agent is so convenient and produces such immediate effects that it is often used by the indolent, careless physician, when other agents would produce better after results, and would more speedily promote a permanent cure. It is, therefore, proper to caution the young physician, against depending, upon it to too great an extent, and to urge him to study well all other agents acting synergistically, so that when his knowledge of the other agents permits him to choose between them he will prefer them. He may thus be able to select an agent with a single direct influence, where, with the administration of this, he has undesirable side influences to overcome in addition to the treatment of the other conditions. Administration—Opium may be administered by the mouth, by the rectum or vagina, by the hypodermic injection of its alkaloids, by application to a portion of the surface of the body after removal of the cuticle, by inhalation or by insufflation. Where there is a temporarily apparent contraindication for its use, the aqueous extract or the deodorized tincture (aqueous) or other aqueous preparations, may be used, as water does not dissolve the narcotine, which is believed to be the irritating and depressing principle of the alkaloids. Or it may be given in conjunction with some agent which will overcome the antagonizing conditions. The inactive secretions may be partially reestablished by pilocarpine or jaborandi, or the bromides may be given in conjunction to soothe the nervous system, or ergot to unload the brain of an excess of blood. The hypodermic use of morphine is demanded and is justifiable where great pain is present. This method is preferable because the chemical influences of the gastric secretions upon the salt are avoided. Veterinarians find it necessary to always administer morphine in this manner, as often no desirable effects are produced if brought in contact with the stomach and intestinal secretions. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 318 Specific Symptomatology—When opium is given carelessly or promiscuously, unfavorable results may occur. The conditions under which the administration of opium or its narcotic salts are admissible are as follows: There is pain without cerebral engorgement; there is an absence of flushed face, but not pallor; there is a relaxed, cool and perhaps moist skin; the tongue is moist and the pupils are not contracted. Extreme wakefulness or restlessness, painful, spasmodic conditions, excessive passive discharges of whatever character and local inflammations with the above conditions all indicate the use of the agent. The agent can often be substituted in mild cases, and with children, and the causes of pain can often be removed by other agents; but severe, persistent, racking pain has no other antidote except anesthesia. It, is, therefore, contra-indicated where there is an irritated and overstimulated nervous system, with flushed face, bright eyes with contracted pupils, dry, hot skin, dry, coated tongue and inactivity of the excretory functions.

Applicability Will the potental soluton be efectve for solving the problem under ideal conditons? If the scope of the study is limited to only a few areas discount zyloprim 100 mg amex, justfy and give reasons why (see no buy 100 mg zyloprim with amex. Learning points:Learning points: The problem analysis chart will guide the directon of the study buy zyloprim cheap online. Draw a centre bubble that contains the problem stated in a negatve manner (the primary bubble) purchase 300 mg zyloprim overnight delivery. In practcal terms the problem analysis is best done by a “brainstorming” session using a fip-chart. Secondary bubbles are then drawn for key factors contributng to the problem and so on. An evaluaton of the glucose-6 phosphate dehydrogenase screening procedure in selected hospitals in Perak. The argument for why we should conduct this research or why the research problem is important should be clearly outlined. The relevant studies identfed during the literature review are also incorporated into the problem statement. Conclude your introducton with a fnal paragraph clearly statng the importance of the problem and what we aim to do. This is a search for published / unpublished work and experts in the area to guide you in planning your study. The literature review should be incorporated into the introducton, methods and discussion. It is important to have a good and systematc method to keep useful artcles and reference them in the text. Reference them according to one of two internatonal standard formats - Vancouver or Harvard styles. Cite artcles used in the text of your proposal/report/publicaton, according to the format selected. Statstcal guidelines for contributors to medical journals Br Med J 1983; 286:1489-1493. Statstcal guidelines for contributors to medical journals Br Med J; 286:1489-1493. Learning points:Learning points: This will help you identfy many things, such as:This will help you identfy many things, such as: •• defnitons of terms. The following table shows some Internet search sites: Name Site Resource Google Scholar htp://scholar. Up-to-date, accurate Medicine gov/database/ informaton about Cochrane Collaboraton htp://www. Clearing House gov/ – a public resource for evidence-based guidelines The Community htp://www. Hand search the relevant journals in a library (useful to examine the December issues) if you have no internet facilites or looking for older publicatons. This refects your problem and defnes the scope of the study (the general objectve). Breakdown your overview into specifc areas addressing diferent aspects of your problem (the specifc objectves). Learning points:Learning points: Objectves clearly state what you plan to do and are a “road map” (keeps study inObjectves clearly state what you plan to do and are a “road map” (keeps study in focus). One of the weaknesses in writng the method is a tendency to just describe the study type without describing the research design adequately. A manager or research commitee will read this secton to see the quality of the scientfc content. Learning points:Learning points: The overview of the research design ensures that there is a clear framework ofThe overview of the research design ensures that there is a clear framework of what the researchers plan to do. If your research objectve is to change the situaton, this requires an interventonal approach. If you plan to evaluate or explain/audit a problem, then use a descriptve approach. Learning points:Learning points: The study type ensures that the appropriate approach is used to answer theThe study type ensures that the appropriate approach is used to answer the research objectves. They describe the distributon of disease in human populaton and investgate possible aetological factors to explain that distributon. The investgators have no control over whom and who is not exposed to the factor under study. Risk factor - Risk Factor + The purpose of the comparison is Control to determine whether, in the past, Risk factor - the cases have been exposed more (or less) ofen to a specifc factor than the controls. These are studies in which the investgators do have control over who is and who is not exposed to the factor under investgaton. Clinical trials are interventonal studies of the efect of a specifc treatment on patents who already have a partcular disease. Partcipaton must be voluntary and respondents allowed to say “No” to partcipaton, or to stop/drop out at any tme. The respondent’s choice not to partcipate must not afect the health care provided. Inform your respondents fully about the study and possible risks, if any (informed consent). Respondents should not be paid for partcipaton (apart from reimbursements for travel expenses, etc. Any confict of interest between the researcher and the study being conducted must be declared. Researchers should not be paid for conductng a study (apart from reimbursements for travel expenses, etc. Learning points:Learning points: Never compromise your respondent’s dignity and safety for research. Defne the scale of measurement you want to use for that variable based on the type of variable Learning points:Learning points: Identfy all variables necessary. Identfcaton of variables will help the investgator to: • specify the important items for study. Figure 6: Relatonship between groups of variables In most “cause” and “efect” studies, we are looking at the relatonship between independent and dependent variable. That is, the “efect/outcome” is the dependent variable, the “cause” is an independent variable. A variable that is associated with both the problem and the possible cause of a problem is a potental confounding variable. The confounding variable may either strengthen or weaken the apparent relatonship between an outcome and a possible cause. Therefore, in order to give a true picture of cause and efect, the confounding variables must be considered, either at planning stage of or during data analysis. Example: In a survey to investgate whether there is a relatonship between mothers who are cigarete smokers and weight of their newborn, the dependent variable is the newborn’s weight, the independent variable is the mother’s smoking habit. Two aspects need to be considered: defne the variables and state the scale of measurement. It should be objectve, observable and is sufciently clear and explicit to avoid ambiguity. The selecton for a scale is determined by the variable itself and the methods available for measuring it. A type of data in which the variables are divided into a number of named categories. Example: • Level of knowledge: poor, average, good; • Opinion of individual: fully agree, agree, disagree, and totally disagree. A type of variable in which there is an unlimited number of equally spaced categories; thus a contnuum of values is possible. Patent has Dengue fever confrmed by serology yes/No/Not available dengue fever (IgM positve or four-fold rise in Igg ttre) or virology. Social class Head of household’s main occupaton Detailed occupaton, as stated by respondent in answer classifed into social to a queston in a structured class I - V questonnaire. Haemoglobin Haemoglobin concentraton in g/dl capillary blood, measured by haemoglobinometer.

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