Arthritis Australia

By J. Masil. Sacred Heart University.

As a result generic aciclovir 400 mg overnight delivery, medical science now has at its disposal an arsenal of therapeutic antibodies that are structurally identical to their natural counterparts in the human body discount 400mg aciclovir visa. Example MabThera: A good example of a highly effective chimeric an- hope for patients with tibody is the Roche product MabThera/Rituxan lymphoma (rituximab). The target protein of this therapeutic antibody is a receptor located on the surface of B lymphocytes (white blood cells), which in lymphomas grow uncontrollably. The antibodies bind to the cancer cells, marking them out for destruction by the body’s immune system. At the same time rituximab makes the cells more susceptible to certain forms of chemotherapy, thus improving the survival chances of patients who previously had no further therapeutic options fol- lowing unsuccessful chemotherapy. A turbocharger for the Therapeutic antibodies such as rituximab help immune system the patient’s immune system to home in on dis- eased target cells. Main avenues of research 47 Enhanced immune response: modified therapeutic antibodies 120 Engineering of antibody 100 80 60 40 Wildtype antibody 20 Engineered negative 0 control antibody 0 10 20 30 40 50 Antibody concentration (ng/ml) Specifically modified therapeutic antibodies can induce a five to eight times stronger immune response (e. The next drug The next step was to link therapeutic antibodies generation: small with small molecules to form what are known as molecule conjugates small molecule conjugates. Antibodies have a disadvantage that they share with other thera- peutic proteins: they are too bulky to penetrate into the interior of cells. Potential targets are therefore limited to molecules lo- cated outside of or on the surface of the body’s cells. By contrast, many conventional, chemically synthesised small molecule drugs can readily pass through the cell membrane to targets within the cell or even the cell nucleus. Small molecule conjugates combine the specificity of therapeu- tic proteins – especially antibodies –with the broad target range of small molecules. To produce them, researchers have de- veloped complexes, or conjugates, consisting of therapeutic antibodies coupled to low-molecular-weight drugs. In such con- jugates the antibody’s role is to ferry the actual drug directly to its target in the body. Drugs commonly used to destroy cancer cells also attack healthy cells in the body. Once Co plexbinds this occurs, the entire conju- tocell gate is internalised in the cell. In cancer cells the anti- body is digested and releases the small molecule, which Cancercell then destroys the diseased cell. In this way cancer cells Cancercell orzelle can be specifically targeted and adverse effects on Co plexcarries drugintocell healthy cells can be minim- ised. If Entireco plexinsidecell the findings from tests are borne out, the latest gener- ation of these drugs could Cancercell signal a breakthrough not Drugkills cancercell only in cancer therapy but in many other therapeutic Conjugated antibodies combine the specificity of thera- areas where medical science peutic proteins with the broad target range of small mole- has hitherto had to contend cules. The antibodies target a specific structure on the with severe side effects surface of cancer cells. Once the antibody has located its target and bound to it, the conjugated small molecule drug caused by the unspecific is released, penetrates the cancer cell and kills it. Spektrum Akademischer Verlag, Heidelberg, 6th edition 2003 Presentations at a media conference: The Roche Group – one of the world’s leaders in bio- tech, Basel, November 2004 http://www. As well as the therapeutic possibilities it offers, modern biotechnology can lead to novel ways of combating diseases such as diabetes, cancer and rheumatic diseases. For example, early and specific diagnosis, and also tests that can monitor treatment and the course of an illness, can result in more effective treatment of patients. The biotechnology market Medical science can only be as good as its under- grows apace standing of disease processes. The more doctors know about the causes of diseases, the more ef- fectively they can deal with them. This realisation may sound simple, but translating it into practice remains difficult, be- cause the critical part of treatment is often finding the right diagnosis. It is precisely in this area that biotechnology has made tremendous strides in recent decades. Thus, for example, alleviating pain should not be the only goal when treating patients with chronic pain. It is only when the source of the pain has been identified that steps can be taken to counter it in the long term. Yet pain patients in particular often have to undergo veritable medical odysseys as a result of uncer- tain diagnoses, failed treatments and ever increasing pain. De- spite having similar symptoms, painful rheumatic diseases can be caused by very different disorders, each of which re- Terms quires a distinct treatment. Whether a treatment is suc- Biopharmaceuticals drugs manufactured using biotech- nological methods. The picture is similar with Genome the (largely unalterable) complement of all genes of cancer, where the sheer va- an organism. Genomics the science concerned with the form, function riety of causes requires a new and interaction of the genes of an organism. A tu- Genotype the variants of a given gene possessed by an mor can remain completely organism; as a rule a human can have no more than two variants of each gene – one from the father and the other from the mother. Proteomics the science that deals with the form, function origin and genetic pattern of and interactions of the proteins of a biological system.

If the drug breakdown process proceeds too quickly purchase aciclovir 400 mg with visa, it leads to a loss of drug efficacy; if it proceeds too slowly buy 400 mg aciclovir with amex, it leads to an in- creased risk of side effects. Doctors can use the AmpliChip test to predict how their patients will react to a drug and adjust their therapy optimally. No genetics laboratory could do without it, and genome sequencing projects, of which there are many, would be inconceivable without it. Many pioneering findings are based, for ex- ample, on the Human Genome Project, in the course of which the human genome was sequenced. A number of 58 follow-on projects are now looking for genetic variation relevant to the development and treatment of diseases. In this way, patients can be tested for sus- ceptibility to a certain hereditary disease, for example. Pre- natal and preimplantation diagnostic tests also make use of the same process. Proteins – information As the most important group of biological sub- carriers par excellence stances, proteins (gene products) are key targets of molecular diagnostics. T Various metabolic proteins serve as the targets of diagnostic tests, because their activity may indicate the presence of cer- tain diseases. Molecular diagnostics uses these tools, among others, to identify genes and proteins associated with diseases. By antibodies against the specific protein being sought are observing the labels it can be determined whether and how attached to a carrier (1). The surplus so- diseases with great specificity, making a precise diagnosis of the underlying disorder all the more important. Particularly in the field of biotechnology, treatment and diagnosis go to- gether hand in glove. Proteins as biomarkers A protein that is suitable for detecting altered in- formation flow in a biological system is called a biomarker. The main areas of research are the major prevalent diseases for which only unsatisfactory diagnostic tests and therefore treat- ment options are available – mainly malignant diseases such as intestinal, lung or breast cancer, and systemic diseases such as rheumatic diseases and diseases affecting the central nervous system, e. What all these disorders have in common is that they lack a clearly defined cause. Rather,they are caused by an unfortunate chain of multiple genetic and envi- ronmental factors. If the disease does develop, early and specific treatment is often life-saving, and this, in turn, de- pends on finding the right diagnosis. Biomarkers can therefore bring about progress at four levels: T Screening markers can help even in the asymptomatic phase to detect the start of the disruption of information flow that is responsible for disease. To ensure that as many people as possible bene- fit from such preventive examinations, the procedures should be as painless, simple and safe as possible. Forms of the same disease that differ in their virulence often require entirely different therapies. For ex- ample, early rheumatic symptoms are usually treated by con- servative methods such as physiotherapy or the use of anti- inflammatory ointments and drugs. In especially rapidly progressing cases, aggressive therapeutic intervention may be indicated, even in early stages, despite an increased like- lihood of side effects. Treatment begins with diagnosis 61 T Stratification markers enable doctors to predict whether and how well a patient responds to a certain type of drug. T Efficacy markers, finally, describe how well a drug is working in an individual patient. Example of cancer The fight against cancer is one of the greatest chal- prevention: early intesti- lenges facing modern medicine. According to an nal cancer detection estimate by the International Agency for Research on Cancer,part of the World HealthOrganization, over 1. Al- though screening programs are in place in most industrialised countries, people do not avail themselves of them to the neces- sary extent. Yet up to 90 percent of all fatal cases of intestinal cancer, says the German Felix Burda Foundation, could be pre- vented in the space of ten years by instituting a program of reg- ular endoscopic checks. The major misgiving is that although intestinal endoscopy is effective, it is also unpleasant and, being invasive,not without its risks. To date there is no screening meth- od that is able to identify high-risk patients simply and safely. The early detection of intestinal cancer still relies for the most part on the results of an occult blood test, which detects hidden (‘occult’) blood in the stool. Depending on the study con- cerned, however, this test fails to identify up to half of positive cases. In addition, one in five patients proves to be healthy after subsequent endoscopy. Given the large number of patients with intestinal cancer, medical researchers are therefore working in- tensively on alternatives to the occult blood test. Suitable screen- ing tests based on protein biomarkers could become available within just a few years. It is now known that over 100 different disorders – some degenerative, some inflammatory – are sub- sumed under the umbrella term ‘rheumatism’.

Lack of Vitamin C was proposed to cause a reduction in connective tissue cheap 800mg aciclovir, inflammatory cells cheap aciclovir 400mg amex, 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.

Fluvoxamine impairs single- dose caffeine clearance without altering caffeine pharmacodynamics discount 200 mg aciclovir with mastercard. Urinary excretion of 6 beta-hydrox- ycortisol and the time course measurement of enzyme induction in man purchase 800 mg aciclovir. Receptor-dependent transcriptional activa- tion of cytochrome P4503A genes: induction mechanisms, species differences and interindividual variation in man. Molecular mechanisms of cytochrome P-450 induction by xenobiotics: an expanded role for nuclear hormone receptors. Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin. Expression and regulation of cytochrome P450 enzymes in primary cultures of human hepatocytes. The use of adult human hepatocytes in primary culture and other in vitro systems to investigate drug metabolism in man. Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes. Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: comparison with rito- navir. Drug interactions in primary care: impact of a new algorithm on risk determination. Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole. Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors, and clinical con- firmation of a predicted interaction with ketoconazole. Ketoconazole inhibition of tri- azolam and alprazolam clearance: differential kinetic and dynamic consequences. Inhibition of triazolam clearance by macrolide antimicrobial agents: in vitro correlates and dynamic consequences. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Time-course of recovery of cytochrome P450 3A function after single doses of grapefruit juice. A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. Variation in furanocoumarin content and new furanocoumarin dimers in commercial grapefruit (Citrus paradisi Macf. Identification of 6 ,7 -dihydrox-0 0 ybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Pomegranate juice does not impair clearance of oral or intravenous midazolam, a probe for cytochrome P450-3A activity: compar- ison with grapefruit juice. Comparative kinetics and response to the benzodiazepine agonists triazolam and zolpidem: evaluation of sex-dependent differences. Kinetics and dynamics of lorazepam during and after continuous intravenous infusion. Age and gender effects on the pharmacokinetics and pharmacodynamics of triazolam, a cytochrome P450 3A substrate. Kinetics and dynamics of single-dose triazolam: electroencephalography compared to the digit-symbol substitution test. Dynamics and kinetics of a modified-release formulation of zolpidem: comparison with immediate-release standard zolpidem and placebo. This increased interest has arisen in part because of many documented adverse clinical consequences of drug-drug interactions, coupled with improved understanding as to their cause. Interest in drug-drug interactions has also increased because of the rise in polypharmacy, where patients may take many drugs in the course of a day. Depending on various short- term conditions, an antibiotic or antifungal might be used. To avoid serious harm, health care practitioners must be aware of and manage potential important interactions. To provide optimum information in product labeling for practitioners and patients, drug development and regulatory 665 666 Huang et al. Further, product labeling for older drugs should be updated as additional information about their potential for being a part of important drug-drug interactions becomes available. Pharmacokinetic drug-drug interactions result from alteration in the dose/ systemic exposure relationship, as reflected in a blood or plasma concentration– time curve, when an interacting drug induces or inhibits one or more routes of elimination or transport of a substrate drug. Inhibition of metabolism may be associated with increased blood levels and pharmacological activity of the sub- strate, but if the substrate is a prodrug, pharmacological activity may be reduced; in some cases, when the parent drug and its metabolite have equal effects, there may be no change in pharmacological activity despite large changes in blood levels of parent and metabolite (Chaps. The magnitude of clinical effect of an inhibitor depends on the magnitude of the effect of the inhibitor on clearance of the substrate, which in turn depends on the extent of inhibition and the extent to which the substrate is cleared by the affected pathway. Drugs that induce meta- bolic pathways and reduce systemic exposure may result in loss of effectiveness (Chaps.