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Evista

By K. Grok. Worcester Polytechnic Institute.

Inhibition of Bacterial Fatty Acid Synthesis Pharmaceutical companies have to a large extent retreated from the field of antibacterial drugs generic evista 60 mg mastercard, concentrating instead on chronic diseases purchase 60 mg evista mastercard, which has market advantages. Earlier, there was a cooperation between the health care and pharmaceuti- cal industries, which has now ceased, particularly regarding antibacterial agents. It was therefore very encouraging that the Merck pharmaceutical company took on the work of character- izing and developing a new approach to antibacterial action. As it turned out, it also became a good illustration of the great risks involved with developing a new antibacterial agent. This particular approach began with a report about a new antibiotic produced by the soil bacterium Streptomyces platensis isolated from a soil sample from South Africa. The finding was the result of a large screening program involving 250,000 extracts from drug-producing microorganisms. Itturnedouttobe a small molecule (molecular mass: 441 Da), consisting of two distinct structural elements: 3-amino-2,4-dihydroxybenzoic acid and lipophilic pentacyclic ketolide, linked together by an amide bond. Platensimycin showed a new mechanism of action, inter- fering selectively with the enzymatic elongation mechanism at the bacterial synthesis of fatty acids, which in sizes of 8 to 18 carbon atoms build bacterial membranes and cell surfaces. It ought to be pointed out here that inhibition of bacterial fatty acid synthesis for antibacterial action was used before in the action of the tuberculostatic agent of isoniazid, discussed in Chapter 9. So far, platensimycin has only been tested in vitro and in preliminary animal experiments with mice, where it showed inhibiting effects against staphylococci and pneumococci similar to those of penicillin against susceptible strains of these bacteria. There is still a long way to a clinically useful agent, and there would be a risk of resistance by mutational enzyme changes. Again it is interesting that the extensive research work regarding platensimycin was performed and the cost defrayed by a large pharmaceutical company, which by economic con- siderations seems to continue research regarding antibacterial agents. To explain the scarcity of new antibacterial agents and the risks involved in their development, the future potential of platensimycin is important to assess. The future use of platen- simycin as an antibiotic was hit by a great disappointment. The biosynthetic machinery of fatty acid formation is encoded by sev- eral bacterial genes involving the fab loci of the bacterial genome. Fab proteins come together to construct fatty acids two carbon atoms at a time in a cyclic process. This biosynthetic pathway is essential for the formation of cellular membranes in many bacte- rial pathogens. The process is distinct from fatty acid biosynthesis in mammalian cells, which suggests that its inhibition in bacteria could be selective. Yet older studies, from the 1970s, showed that bacteria could acquire fatty acids from their surroundings and incorporate them into their cell membranes. In a recent report, evidence was presented to question antibiotic therapies that target fatty acid biosynthesis. Inhibitors of fatty acid syn- thesis were quite effective at inhibiting the growth of pathogenic strains resistant to other antibiotics in standard laboratory media (which lack fatty acids), but this effect was abolished when fatty acids were added or when human serum, which is rich in fatty acids, was added. These observations would raise the bar for target validation not only for platensimycin but for future drug discovery in general. The authors of this report define what they call the resistome, comprising a gigan- tic collection of antibiotic resistance genes among soil-living microorganisms. This concept of the resistome will dramatically reshape our approach to finding new antibacterial drugs. There is abundant information regarding soil bacteria producing and encountering large amounts of antibiotics, which has meant that these organisms have evolved corresponding sensing and evad- ing strategies. It is a fact that most clinically relevant antibiotics originate from soil-dwelling actinomycetes. Antibiotic produc- ers harbor resistance elements for self-protection, which are often found together with antibiotic biosynthetic operons. Genes ortol- ogous to these have been observed on mobile genetic elements in resistant pathogenic bacteria isolated from patients. For example, and as mentioned earlier, aminoglycoside- modifying enzymes (Chapter 6) and the lactate-substituting machinery making the peptidoglycan synthesis insensitive to vancomycin probably originated in soil-dwelling antibiotic pro- ducers (Chapter 5). The presence of antibiotics in the environment has been shown to promote the acquisition or independent evo- lution of specific resistance elements in soil organisms in the absence of innate antibiotic production. The soil could thus be looked at as a large reservoir for resistance, the largest part of which might not yet have emerged in clinically important bac- teria. The report mentioned is a systematic study of 480 morpholog- ically different soil microbes regarding their resistance to 21 different antibacterial agents, including natural products such as vancomycin and erythromycin, and also completely synthetic molecules such as quinolones, sulfonamides, trimethoprim, and linezolid. Many of the agents tested were well established, but importantly, antibacterial drugs that have only recently been approved for clinical use were also tested. Astonishingly, every isolate was found to be multidrug resistant to seven or eight antibiotics on average, with two strains being resistant to 15 of the 21 antibacterial agents tested. Interestingly, five of the vancomycin-resistant soil microbe isolates were, by the use of polymerase chain reaction, shown to carry the cluster of three genes that in clinical isolates of vancomycin-resistant pathogenic bacteria has been shown to mediate resistance to this drug. Despite the lack of known prior exposure to fluoroquinolones, some 10% of the soil microbes in the study demonstrated intrinsic resistance to ciprofloxacin. All the soil microbe strains were resistant to the synthetic agent trimethoprim, which as mentioned earlier, works by inhibiting the bacterial dihydrofolate reductase.

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Does the patient report bleeding during simple daily activities buy generic evista 60 mg on-line, such as brushing his/her teeth? Past Medical History Is there a history of liver dysfunction buy discount evista 60 mg online, such as hepatitis or cirrhosis (with associated decrease in synthetic function and decrease in coagu- lation factors in the intrinsic pathway), or a history of renal failure with its associated dysfunctional platelets? Medications Multiple medications affect coagulation by a variety of mechanisms (Table 8. This effect is overcome only by new platelet synthesis over a period of 7 to 10 days. Deficiencies of the various factors generally must be moderate to severe to affect clinically on bleeding. Operative History A complete understanding of what operation was performed and the technical details is critical in dealing with a postoperative bleeding problem. Significant, bright red bleeding from a surgical wound might represent a suture line leak and require reexploration. Alternatively, if there were many adhesions that were divided at the time of surgery, these can be a source of postoperative bleeding. What medications or blood products did the patient receive while in the operating room? If the patient received large-volume transfusions with packed red cells, clotting factors and 140 G. Citrate used to anticoagulate banked blood binds calcium, and calcium is necessary as a cofactor in multiple steps of both the intrinsic and extrinsic pathways (Fig. Bright red blood (well oxygenated) from the surgical incision suggests an arterial source. If bleeding is suspected, a complete phys- ical exam may yield clues to occult bleeding. However, in obese patients, soft tissues can mask a significant amount of bleeding. Fur- thermore, the chest, abdomen, pelvis, and retroperitoneum all may hold significant amounts of blood, with only subtle clues to the exam- ining healthcare practitioner. If a thoracic operation was performed, the chest should be auscultated carefully and percussed for dullness, and the chest tube output should be inspected for quality (sanguinous vs. If an abdominal operation was per- formed, abdominal pain, girth, and signs of flank ecchymosis should be evaluated. Surgical Bleeding and Hemostasis 143 Diagnostic Studies After taking a history and performing a physical exam, the clinician should have narrowed the differential diagnosis. Laboratory tests will be helpful in confirming the diagnosis and managing the patient appropriately with respect to blood loss. The amount of blood loss usually is well represented by the decrease in hemoglobin and hematocrit. However, in the setting of acute blood loss, the hemo- globin and hematocrit are not accurate, as they take some time to equi- librate after acute blood loss. For example, the patient in our case may have a hemoglobin of 10g/dL (intraoperative hemoglobin of 11g/dL), low urine output, and significant bloody drainage from an incision site. However, once her intravascular volume has been restored and the hemodyamics are corrected with crystalloid, she will have a much lower hemoglobin. Platelet Counts Platelet counts are affected by a variety of causes as well as medica- tions (Table 8. Heparin, ranitidine, or cimetidine cause thrombocy- topenia in some patients and should be discontinued if platelet counts decline during their use. Postoperative bleeding in the setting of moderate to severe thrombocytopenia mandates platelet transfusions. However, a normal platelet count is not synonymous with normally functioning platelets. As mentioned above, aspirin affects the platelet function without a change in platelet count. A standardized injury at the skin level is created with an automatic lancet, and the amount of time necessary to clot is the bleeding time. It measures the adequacy of coagulation factors as well as platelet function, thus taking 144 G. Common causes for abnormalities in coagulation screening tests and sugges- tions for initial further analysis. Surgery: Basic Science and Clinical Evidence, New York: Spinger-Verlag, 2001, with permission. Also, patients with uremia may have platelets that do not function properly, yet their platelet count may be normal. Hepatitis, passive liver congestion, cir- rhosis, and hepatic ischemia all can result in hepatic dysfunction, decreased protein synthesis, and abnormal coagulation. An elevated alkaline phosphatase may suggest biliary obstruction and an associated decrease in vitamin K–dependent factors.

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These advances provided large quantities of new biopharmaceuticals 60mg evista with mastercard, such as peptides discount evista 60mg with visa, proteins and antisense oligonucleotides, which generally possess inherent disadvantages for drug delivery. Disadvantages include such properties as large molecular size, hydrophilicity and instability, making these “new biotherapeutics” unsuitable for oral delivery. Generally such drugs must be given by the parenteral route, which has many associated disadvantages, as mentioned above. Recent research has been directed towards the use of alternatives to the parenteral route, for drugs (including the “new biotherapeutics”) that cannot be delivered orally. Potential alternative portals of drug entry to the systemic circulation include the buccal, sublingual, nasal, pulmonary and vaginal routes. These routes are also being studied for the local delivery of drugs directly to the site of action, thereby reducing the dose needed to produce a pharmacological effect and also possibly minimizing systemic side-effects. Drug delivery technology is becoming increasingly sophisticated and current approaches take into account such factors as the influence of pharmacokinetic processes on drug efficacy, as well as the importance of drug timing and of drug targeting to the site of action. Emerging technologies are addressing a variety of issues, including bio-responsive drug release and the delivery of nucleic acid therapeutic entities. This book is concerned with the various routes of delivery under investigation, and these new and 3 emerging delivery technologies. However, a full appreciation of these concerns cannot be gained without first understanding: • the concept of bioavailability; • the process of drug absorption; • the pharmacokinetic processes; • the importance of timing for optimal drug therapy; • delivery considerations for the “new biotherapeutics”; • the limitations of conventional therapy. This chapter provides an overview of these considerations and highlights the necessity for advanced drug delivery systems, in order to optimize drug efficacy. In terms of drug efficacy, the bioavailability of a drug is almost as important as the potency of the active agent itself. Measuring a drug’s bioavailability thus involves measuring the rate and extent of drug absorption. This is ideally measured in terms of the clinical response of a patient; however, only a minority of clinical responses, such as blood pressure, can provide accurate quantitative data for analysis. A further method of assessment is the measurement of the drug concentration at the site of action; however, this cannot be achieved practically. For clinical purposes, it is generally accepted that a dynamic equilibrium exists between the concentration of drug at the site of action (C ) and the concentration of drug in blood plasma (C ). Thus Cs p p is generally used as an indirect indicator of the concentration of drug at its site of action and the most# commonly used method of assessing the bioavailability of a drug involves the construction of a Cp versus “Time” curve (Cp vs T curve). A typical Cp vs T curve following the administration of an oral tablet is given in Figure 1. At zero time (when the drug is first administered), the concentration of drug in the plasma is zero. As time proceeds, more and more of the drug starts to appear in the plasma, as the drug is gradually absorbed from the gut. Following peak levels, the concentration of drug in the plasma starts to decline, as the processes of drug distribution and drug elimination predomi-nate. Thus a profile of the rate and extent of drug absorption from the formulation over time is obtained. Formulation B has a slower onset of therapeutic action, but the therapeutic effect is sustained longer than that obtained with formulation A. Formulation C demonstrates both a slow rate and extent of absorption, in comparison to the other two formulations. Relative Bioavailability is the comparison of the rate and extent of absorption of two formulations given by the same route of administration. A study of relative bioavailability generally involves the comparison of a 4 Figure 1. For example, the bioavailability of a new tablet formulation of a drug for oral administration can be compared with the oral bioavailability of the brand leader tablet formulation. The relative bioavailabilities may be calculated from the corresponding Cp vs T curves as follows: (Equation 1. In contrast, Absolute Bioavailability involves comparison of the drug’s bioavailability with respect to the corresponding bioavailability after iv administration. Absolute bioavailability may be calculated by comparing the total area under the Cp vs T curve obtained from the absorption route in question (often the oral route, although the approach can be used for other routes, such as the nasal, buccal, transdermal routes etc. In contrast, a drug administered via any other route (intramuscular, subcutaneous, intestinal, rectal, buccal, sublingual, nasal, pulmonary and vaginal) will have to circumvent various physical and chemical barriers (discussed below), so that the bioavailability will be lower in comparison to that obtained after iv administration. For example, to achieve 100% bioavailability via the oral route requires the drug to: • be completely released from the dosage form into solution in the gastrointestinal fluids; # Using C as an indicator of C is obviously a simplification that is not always valid and the relationship cannot be used p s without first estabkishing that C and c are consistently related. As many drugs bind in a reversible manner to plasmap s protenis, a more accurate index of C is the concentration of the drug in protein-free plasma Cs pfp.

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Probably it will prove useful in all diseases of mucous membranes purchase evista 60 mg otc, where there is profuse secretion order 60mg evista free shipping. A glucoside, or neutral principle, is obtained from several species of willow, which will serve an important purpose in medicine when well studied. As an anti-periodic it has proven so uncertain as to have almost fallen into disuse, though, if the case is rightly diagnosed, it will be found superior to quinine in the few cases where it is indicated. It has also fallen into disuse for the purposes of an ordinary bitter tonic and restorative. The case in which I should recommend it is the one showing distinct periodicity, with rheumatic pain. We prefer the acid prepared from oil of wintergreen to that made from carbolic acid, as it is less irritating, and better borne by the stomach in its internal use, and a more bland local application. The dose will vary from the fraction of a grain to five grains; as an anti-rheumatic, two grains every two hours, until ten or twelve grains are taken. In some cases the remedy will serve a better purpose if given in solution as a salicylate of potash or soda. As a local application, we combine it with borax, or chlorate of potash, both rendering the acid soluble in water. We use it with marked advantage as a spray in chronic nasal catarrh, chronic pharyngitis, and as an injection in some cases of leucorrhœa or gleet. Whilst this, as well as other varieties of the willow, possesses feeble tonic and antiperiodic properties, there are so many better remedies of this class that it would be well to dispense with its use altogether, had it no other action. But there is a class of cases in which the Salix is a very decided antiperiodic, and if these can be distinguished, the remedy will be valuable. I believe it is in those in which there is increased secretion from mucous membranes, and especially where there is the septic tendency, marked by fetid discharges, foul tongue, etc. In typhoid disease it may be employed both as a tonic and antiseptic, using the smaller dose named. The remedy is easily prepared, and may well replace some inferior articles that have hitherto been employed. The Sage exerts a tonic influence on the skin, and to a less extent upon the kidneys and mucous membranes. We employ it where the skin is soft and relaxed, with an enfeebled circulation and cold extremities. In the treatment of colliquative perspiration it answers an excellent purpose, if the condition above is maintained. If, however, the night sweat is preceded with hectic fever, and a dry, harsh skin, it will be useless. It will prove a good remedy in increased secretion of urine of low specific gravity; in such cases it may be associated with belladonna. It may also be associated with the bitter tonics in all cases in which there is atony and increased secretion from mucous membranes. It may be employed for the general purposes of an alterative - increasing waste, in syphilis, scrofula, and other diseases attended by deposits or depravation of tissues. It is especially useful in those cases where there is an œdematous condition, or fullness of tissue from an increased amount of water. We meet a case of chronic disease occasionally, in which the tissues are full and flabby, evidently from too much water; in these Sambucus is a good remedy. It may be employed in dropsy, though its action is not so decided as the Apocynum. As a local application the Sambucus is specific to those eruptions that arise on full tissues (as above), and are attended with abundant serous discharge. Thus in some forms of eczema, especially eczema infantilis or milk scall, and in the above form of the disease, it will alone effect a cure. We also employ it in idolent ulcers, with soft œdematous borders, and serous secretion, and in mucous patches with free secretion. An ointment is prepared by simmering the inner bark in fresh butter (old style), or a glycerole may be made, with the addition of the usual quantity of starch. Nitrate of Sanguinarina is a valuable preparation, and may be dispensed in syrup, in the proportion of grs. This use is valuable in bronchitis with increased secretion, and in atonic conditions of stomach and bowels with increased secretion of mucus. In minute doses we employ it in cases of cough with dryness of the throat and air passages, feeling of constriction in the chest, difficult and asthmatic breathing, with sensation of pressure. In the same doses it is a stimulant to the vegetative system of nerves, and under its use there is an improvement in the circulation, in nutrition, and secretion. As a remedy in diseases of the respiratory tract, I prefer the Nitrate of Sanguinarina to the tincture. It evidently exerts a direct influence upon the nervous system, relieving irritation, and this probably extends to the sympathetic. It would be well to give it a trial in those cases in which there is enfeebled function with nervous irritability. The action is very similar to that of copaiba, but it is thought less offensive to taste and smell, though both are very persistent.

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