By S. Benito. Valparaiso University.

In addition 20 mg forzest sale, older adults Tumor necrosis factors (TNF) are produced by activated have increased blood levels of antibodies against their own macrophages and other cells and act on many immune and tissues (autoantibodies) 20 mg forzest fast delivery. They participate in the inflamma- Impaired immune mechanisms have several implications tory response and cause hemorrhagic necrosis in several for clinicians who care for elderly patients, including the types of tumor cells. TNF-alpha is structurally the same following: as cachectin, a substance associated with debilitation and • Older adults are more likely to contract infections and weight loss in patients with cancer. When an infection develops in INFLUENCE IMMUNE FUNCTION older adults, signs and symptoms (eg, fever and drainage) may be absent or less pronounced than in younger Age adults. Thus, achieving protective antibody titers may re- During the first few months of gestation, the fetal immune quire higher doses of immunizing antigens in older system is deficient in antibody production and phagocytic adults than in younger adults. During the last trimester, the fetal immune system • Older adults often exhibit a less intense positive reac- may be able to respond to infectious antigens, such as cy- tion in skin tests for tuberculosis (indicating a decreased tomegalovirus, rubella virus, and Toxoplasma. In the placenta, maternal blood and fetal blood Nutritional Status are separated only by a layer of specialized cells called tro- phoblasts. Because antibodies are too large to diffuse across Nutritional status can have profound effects on immune func- the trophoblastic layer, they are actively transported from tion. Adequate nutrient intake contributes to immunocompe- the maternal to the fetal circulation by the trophoblastic tence (ability of the immune system to function effectively). A severe lack At birth, the neonatal immune system is still immature, of calories or protein decreases numbers and functions of but IgG levels (from maternal blood) are near adult levels T cells, complement activity, neutrophil chemotaxis, and in umbilical cord blood. An inadequate zinc intake can depress the func- antibodies is severed at birth. Zinc is a cofactor for many enzymes, 638 SECTION 7 DRUGS AFFECTING HEMATOPOIESIS AND THE IMMUNE SYSTEM some of which are found in lymphocytes and are required for autoimmunity develops from several events rather than lymphocyte function. Zinc deficiency also may result from in- a single one adequate absorption in the GI tract or excessive losses in urine, • In immunodeficiency disorders, the body is especially feces, or through the skin with such disorders as chronic renal susceptible to infections and neoplastic diseases. Vitamin is a major immunodeficiency disorder that decreases the deficiencies may also depress T- and B- cell function because numbers and almost all functions of T lymphocytes and several (eg, A, E, folic acid, pantothenic acid, and pyridoxine) several functions of B lymphocytes and monocytes. Immunodeficiency also is induced by severe malnutri- tion, cancer, and immunosuppressant drugs. This effect could result from immunodeficiency states or There is evidence that stress depresses immune function and from cancer cells that are overwhelming in number or therefore increases risks for development of infection and highly malignant. The connection between the stress response and the cell division, but few survive or lead to cancer. Most mu- immune response is thought to involve neuroendocrine mech- tant cells simply die; some survive but retain the normal anisms. The stress response is characterized by increased activ- controls that prevent excessive growth; and some are ity of catecholamine neurotransmitters in the central and destroyed by immune processes activated by abnormal autonomic nervous systems (eg, norepinephrine, epinephrine) proteins found in most mutant cells. Cortisol and other corticosteroids are well known to sup- DRUGS THAT ALTER HEMATOPOIETIC press immune function and are used therapeutically for that purpose. The immune response is affected by these neuro- AND IMMUNE RESPONSES endocrine influences on lymphoid organs and lymphocyte functions because lymphocytes have receptors for many Several hematopoietic and immune cytokines have been syn- neurotransmitters and hormones. Hematopoietic agents are used to prevent or treat symptoms (eg, anemia, neutropenia) caused by disease processes or their treatments. IMMUNE DISORDERS Drugs that modify the immune system are used to prevent or treat infections, treat immunodeficiency disorders and can- Dysfunction of the immune system is related to many differ- cer, and to prevent or treat rejection of transplanted tissues or ent disease processes, including allergic, autoimmune, im- organs. Each of these is Methods include administering exogenous antigens (eg, im- described in the following list to assist in understanding the munizations and desensitization procedures), strengthening use of drugs to alter immune functions: antigens (eg, an antigen that is too weak to elicit an immune re- • In allergic disorders, the body erroneously perceives nor- sponse), or suppressing the normal response to an antigen. In mally harmless substances (eg, foods, pollens) as anti- desensitization procedures, weak extracts of antigenic sub- gens and mounts an immune response. More specifically, stances (eg, foods, plant pollens, penicillin) are prepared as IgE binds to antigen on the surface of mast cells and drugs and administered in small, increasing amounts so the pa- causes the release of chemical mediators (eg, histamine) tient develops a tolerance for the substances and avoids serious that produce the allergic manifestations. Most of these disorders occur more often in women than men, possibly because of 1. What is the difference between innate and acquired hormonal differences. Where are T lymphocytes formed, and what are their SELECTED REFERENCES functions? What is complement, and how does it function in the physiology: Concepts of altered health states, 6th ed. Discuss ways to promote immunization of all promoting health and preventing disease. Critical Thinking Scenario A young couple brings their 6-week-old infant to the clinic for a well-baby check and her required shots. They have lots of questions and ask whether all those shots are really necessary. Basic information regarding immunizations that every new parent should have. Teaching regarding what the parents may expect for 2 to 3 days after the injection and appropriate symptom management. OVERVIEW used for many years contained live virus and caused viral shedding and a few cases of polio. The main dis- Immune responses and types of immunity are described in advantages of IPV are that it must be injected and it is Chapter 42. Early sci- • Hepatitis B virus (HBV) infection can cause serious entists observed that people who contracted certain diseases liver diseases such as acute and chronic hepatitis, cir- were thereafter protected despite repeated exposure to the rhosis, and hepatocellular carcinoma. As knowledge evolved, it was discovered that pro- of HBV may be asymptomatic reservoirs for viral trans- tection stemmed from body substances called antibodies, and mission. Children who become infected are at high risk that antibodies could also be induced by deliberate, controlled of becoming chronically infected. Subsequently, immunization tech- cumstances, hepatitis B vaccine is now recommended niques were developed. Overall, been used, the development of immunizing agents and rec- the goal is to achieve universal immunization, decrease ommendations for their use continue.

Critical Thinking Scenario Georgia Sommers discount forzest 20mg with visa, a 39 year-old mother of 4 cheap forzest 20 mg with amex, is diagnosed with breast cancer that was detected by routine mammography. She is recovering from a modified radical mastectomy when she comes to the clinic to dis- cuss additional treatment with chemotherapy with the oncologist. He explains that she will receive combina- tion therapy with three drugs on a cycle of every 4 weeks. The normal cell cycle is the interval between the birth of a cell and its division into two daughter cells (Fig. Oncology is the study of malignant neoplasms and their treat- The daughter cells may then enter the resting phase (G0) or ment. Drugs used in oncologic disorders include those used to proceed through the reproductive cycle to form more new kill, damage, or slow the growth of cancer cells, and those used cells. Normal cells are also well differentiated in appearance to prevent or treat adverse drug effects. In- ment modality for cancer, along with surgery and radiation stead, they occupy space and take blood and nutrients away therapy. They grow in an uncontrolled fashion characteristics of cancer are described below. They are undifferentiated, which means they have lost the structural and functional character- NORMAL AND MALIGNANT CELLS istics of the cells from which they originated. They are loosely connected, so that cells break off from the primary Normal cells reproduce in response to a need for growth or tumor and invade adjacent tissues. Loose cells also enter tissue repair and stop reproduction when the need has been blood and lymph vessels, by which they circulate through the 913 914 SECTION 11 DRUGS USED IN SPECIAL CONDITIONS mutations of normal growth-regulating genes called proto- G0 oncogenes, which are present in all body cells. Normally, proto-oncogenes are active for a brief period in the cell re- G1 productive cycle. When exposed to carcinogens and genetically altered to oncogenes, however, they may operate continuously and cause abnormal, disordered, and unregulated cell growth. Unregulated cell growth and proliferation increases the prob- ability of neoplastic transformation of the cell. Tumors of the breast, colon, lung, and bone have been linked to activation of oncogenes. M S Tumor suppressor genes (anti-oncogenes) normally func- tion to regulate and inhibit inappropriate cellular growth and proliferation. Abnormal tumor suppressor genes (ie, absent, damaged, mutated, or inactivated) may be inherited or re- sult from exposure to carcinogens. When these genes are in- activated, a block to proliferation is removed and the cells begin unregulated growth. One tumor suppressor gene, p53, G2 is present in virtually all normal tissues. When cellular de- oxyribonucleic acid (DNA) is damaged, the p53 gene allows Figure 64–1 Normal cell cycle. The normal cell cycle (the interval be- time for DNA repair and restricts proliferation of cells with tween the birth of a cell and its division into two daughter cells) in- volves several phases. Mutations of the p53 gene, a common ge- 0 usual functions except replication; that is, they are not dividing but are netic change in cancer, are associated with more than 90% of capable of doing so when stimulated. Different types of cells spend small-cell lung cancers and more than 50% of breast and different lengths of time in this phase, after which they either reenter colon cancers. Mutant p53 proteins can also form complexes the cell cycle and differentiate or die. During the first active phase (G1), with normal p53 proteins and inactivate the function of the ribonucleic acid (RNA) and enzymes required for production of de- oxyribonucleic acid (DNA) are developed. During G2, RNA is synthesized, Thus, activation of oncogenes and inactivation of anti- and the mitotic spindle is formed. Mitosis occurs in the final phase oncogenes probably both play roles in cancer development. The resulting two daughter cells may then enter the resting phase Multiple genetic abnormalities are usually characteristic of (G0) or proceed through the reproductive cycle. Overall, evidence indicates that neoplastic transformation is a progressive process involving several generations of body and produce additional neoplasms at sites distant from cells, with each new generation becoming more like malig- the primary tumor (metastasis). Thus, malignancy probably results from a combi- A malignant cell develops from a transformed normal cell. One The transformation may begin with a random mutation (ab- factor may be a random cell mutation. However, mutations normal structural changes in the genetic material of a cell). A and malignancies are increased in people exposed to certain mutated cell may be destroyed by body defenses (eg, an im- chemical, physical, or biologic factors, especially in large mune response), or it may replicate. Some carcinogens and divisions, additional changes and mutations may produce risk factors are listed in Box 64–1. Once a cancer develops, cells with progressively fewer normal and more malignant factors influencing the growth rate include blood and nutri- characteristics. It usually takes years for malignant cells to ent supply, immune response, and hormonal stimulation produce a clinically detectable neoplasm. CANCER Classification of Malignant Neoplasms The term cancer is used to describe many disease processes Malignant neoplasms are classified according to the type of with the common characteristics of uncontrolled cell growth, tissue involved, the rate of growth, and other characteristics. Leukemias are cancers of the bone marrow genes that regulate cell growth and mitosis, or lack of tumor characterized by overproduction of abnormal white blood cells.

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There might be suspicions that herbal prepa- Adverse effects detected at the post-market rations might lead to drug dependence cheap forzest 20 mg with mastercard. Apart Phase IV might be particularly important for Chi- from a few opium-related herbs generic forzest 20 mg online, Chinese herbs nese medicine trials. Since herbal preparations in fact are well known to be non-addictive do not have clear, definite information about the because of their gross lack of specificities. The large trial popu- obvious that adverse effects in clinical trials lation during Phase IV gives a better chance of using Chinese medicine in fact follow closely the elimination of bias and allows a better oppor- experience encountered in other drug trials. As far as the grading of adverse effects is During the Phase IV trial, the following aspects concerned, it would be appropriate to categorise would deserve particular attention: the effects as mild, moderate and severe. Examples of Herb-Drug Interaction Herb Drug Interaction Mechanism Radix Salviae Warfarin Increased INR Danshen decreases Miltiorrhizae Prolonged PT/PTT elimination of Warfarin (Danshen) in rats Radix Angelicae Warfarin Increased INR and Danggui contains Sinensis (Danggui) widespread bruising coumarins Ginseng (Radix Ginseng) Alcohol Increased alcohol Ginseng decreases the clearance activity of alcohol dehydrogenase and aldehyde dehydrogenase in mice Garlic Warfarin Increased INR Post-operative bleeding and spontaneous spinal epidural haemorrhage Herbal ephedrae (Ma Pargyline, Isoniazid, Headache, nausea, Pargyline, Isoniazid, and Huang) Furazolidone vomiting, bellyache, Furazolidone interfere blood pressure with the inactivation of increase noradrenalin and dopamine; ephedrine in herbal ephedrine can promote the release of noradrenalin and dopamine Ginkgo Biloba Aspirin Spontaneous hyphema Ginkgolides are potent inhibitors of (PAF) Cornu cervi adrenomimetic Strengthens the effect of Natural MAOIs in Cornu pantotrichum Fructus increasing blood cervi pantotrichum, crataegi pressure Fructus crataegi and Radix polygoni multiflori inhibited the metabolism of adrenomimetic, levodopa and opium Radix polygoni multiflori Levodopa Increased blood pressure and heart rate Opium Central excitation Bitter melon Chlorpropamide Decreased urea glucose Bitter melon decreased the concentration of blood glucose Liquorice Oral contraceptives Hypertension, oedema, Oral contraceptive may hypokalaemia increase sensitivity to glycyrrhizin acid St. The requirement for of comparisons before results can be instruc- treatment and the financial implications are tive. More thorough studies at Phase IV should be considered according to epidemiological prin- ciples. Cohort studies might be con- venient and useful, but there need to be While clinical trials aim at a thorough scien- markedly obvious differences between series tific understanding of the effectiveness of specific 74 TEXTBOOK OF CLINICAL TRIALS forms of treatment, endpoints of measurement rehabilitation underway. Different specialties and are set to give objective standards of evaluation. Changes of ally they are adopted right away or after vali- primary endpoints illustrate the efficacy directly. Hence there are charts already developed Secondary endpoints are supplementary crite- for children and the elderly, and different med- ria created to support observations on changes ical specialties and subspecialties likewise have and efficacy. Just to mention a few, important when, predictably, primary endpoints special QoL charts are available for the men- do not give clear-cut, impressive results. Sec- tally ill, cardiovascular diseases, rheumatologi- ondary endpoints become more important when cal disease, respiratory problems, gynaecological problems and special infections. Since Chinese medicine, under most circum- stances, does not operate via a direct confronta- WHAT ARE THE RECOMMENDATIONS FOR tion route but rather acts indirectly to support CLINICAL TRIALS OF CHINESE MEDICINE? QoL often measures the competency ARE THERE UNIQUE FEATURES THAT NEED of the care and the ethical standard of the TO BE OBSERVED? There are features related to health which are Not infrequently, using technical endpoints as derived from the philosophy of Chinese medicine results of clinical trials a reasonable outcome ever since its initial development. Chinese people is observed, and yet patients might not be sat- in all walks of life are influenced by this isfied with their QoL. QoL is therefore multi- philosophy without being aware of it at all stages focal: it differs between developed and under- of their life. The belief that health depends on developed areas, it also differs under differ- a harmony between contrasting forces prompts ent cultural circles. The feeling is QoL charts are also being planned, examined and subjective, but in any clinical trial including the validated. COMPLEMENTARY MEDICINE 75 EXAMPLES OF CLINICAL TRIALS ON CHINESE MEDICINE parallel study. Patients will be randomised to one of the four treatment groups and To give more solid information about clinical treated for a duration of 6 months. Compound • The primary safety endpoint is tolerabil- Title of Study: A Prospective Randomised, ity. Double-Blind, Placebo-Controlled, Parallel • Tolerability failure is defined as a per- Study to Evaluate the Effect of Phyllanthus manent discontinuation of Phyllanthus SP. Compound in the Treatment of Chronic PLUS as the result of an adverse event. Study Centre: Single-centre • The secondary endpoint is HbeAg nega- tive, anti-Hbe positive and a decrease in Objective: ALT level from baseline. Primary Study Regimen: Subjects will be randomly • To evaluate the efficacy of normalisa- and alternatively assigned to receive Phyl- tion of liver enzyme, seroconversion of lanthus PLUS or placebo for 6 months HbeAg and disappearance of HBV DNA prospective parallel study. Statistical Methods: Efficacy: Summary Secondary statistics for the change of HBV DNA, • Proportion of patients with end-of-treat- HbsAG, HbeAg and ALT from baseline ment HbeAg seroconversion (HbeAg will be generated and provided for each to anti-Hbe, normalisation of ALT and treatment group. Change • Proportion of patients with undetectable from baseline in vital signs will be HBV DNA. Title of Study: A Randomised, Double- Blind, Comparison Study of the Effect of Study Regimen: Subjects will be randomly Danggui Buxue Tang with Oestradiol on and alternatively assigned to receive Dang- Menopausal Symptoms and Quality of Life gui Buxue Tang or placebo for 6 months. Duration of Treatment: 6 months treat- Study Centre: Single-centre ment period and 18-month follow-up. Objective: Statistical Methods: Primary • Data will be processed to give group • To compare the effects of Danggui mean values and standard deviations Buxue Tang with Oestradiol on meno- where appropriate. Group differences Tang in patients with menopausal symp- with an error probability of less than 5% toms. Design: A single-centre, randomised, dou- ble-blind and comparison study. Subjects Synopsis III will be randomised to one of the two treat- ment groups and treated for a duration of Name of Study TCM: Danggui Buxue 6 months with follow-up of 18 months. Tang Study Population: A minimum of 100 Title of Study: A Randomised Comparison patients with menopausal symptoms will be Study of the Effect of Danggui Buxue Tang enrolled, 50 subjects per treatment group. Tolerability failure is defined as COMPLEMENTARY MEDICINE 77 Objective: Danggui Buxue Tang or Tranexamic acid for 6 months treatment and 24 months Primary follow-up. Mann–Whitney U- test will be used to compare the differ- • To evaluate the improvement of anaemia.

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I would also continue to follow the guide of Carl Rogers and be in the world of Florence forzest 20mg generic. She told me early that she was absolutely convinced that she had a very rare disease that was beyond medical science 20 mg forzest fast delivery. I was going 74 Symptoms of Unknown Origin to find out what was wrong with her. Te use of that phrase was and still is a popular way of dealing with patients with many symptoms. I always thought it insulting to tell someone so miserable with so many symptoms that nothing is wrong. De- spite the compelling logic against its use, it continues to be a popu- lar phrase for trying to deal with these very difficult patients. I also resisted the common course of telling such a patient that the problem was all in your head. You mean, if I just quit imagining those symptoms, they will just go away? Te foremost reason was that I truly did not know what pa- tients like Florence suffered from. In fact, I began to believe that each such patient suffered from something very different from the other, that there was no one disease or even a group of diseases responsible. I came to believe that each patient suffered idiosyncratically of his or her own peculiar difficulty. How could I with any accuracy say that there was nothing wrong, or that it was just something in their head? I did not know what they had and until I did, I would tell them I did not know. Tere were at least two other prevailing strategies for dealing Florences Symptoms 75 with patients with many symptoms. Te first, and the most dan- gerous, was to make a diagnostic error and assign a false diagno- sis to the patient. Tere are very few tragedies as serious as those that occur when an operation a patient did not need in the first place does permanent harm: Tus my obsession with not as- signing a diagnosis I could not prove. Te other common way of dealing with these patients was to make up an innocuous diagnosis and assign it to them. Each has a counterpart dis- ease that is real but difficult to substantiate, or not too serious, or not life threatening, or trivial even when proven. Most do not have a clean lab test or procedure to prove their exis- tence or absence. I do not mean to demean these conditions, but they are so often assigned that they have come to be almost mean- ingless for many physicians. Te assignable diagnoses I am think- ing about are colitis, spastic colon, dropped kidney, hiatus hernia, sinus (without specifying itis or any other describer), bronchitis, migraines, allergies of all sorts (especially allergies to foods), gastri- tis, or gastroenteritis. It is fair to say that this is the most com- mon method for dealing with a patient with many ill-defined symp- toms. What I was attempting with Florence was to abandon all these common approaches, stay completely honest, and see where it led. I would try to avoid making a diagnostic error and recommending an operation or drugs for some disease I overdiagnosed. I would also not make up some diagnosis just to satisfy my need for one or to give Florence a sense of certainty about her symptoms when no certainty existed. And there was one final thing I would try: I would tell Florence in great detail what I knew she did not have. I now had a very long list of diseases I knew she did not have, and in some sessions, I would read the list very slowly to her. I would say, I now know you do not have tuberculosis or histoplas- mosis or any of the deep fungal infections. You do not have adrenal insufficiency, or adrenal hyperfunction or pituitary hypo- or hy- perfunction. You do not have mitral valve disease or pulmonary valve disease or aortic valve disease. She read constantly and had focused much of her recent reading on the medical literature, which she had access to through the gradu- ate library. She was a constant challenge, bringing me articles and references about different diagnostic possibilities. Each time, I me- thodically went through why she did not have the latest disease she had found in the literature. In some cases, I actually ordered the test that would confirm or refute the suggested disease. Many of them were tropical diseases or infestations unknown in the United States. On a number of occasions, I tested her stool for worms of various sorts, even though I thought it highly unlikely that she had any of them or that they could be causing the symptoms she had. I learned a lot of medicine from Florence and thanked her for her Florences Symptoms 77 efforts. All I could do was keep trying to take the most complete history I could on her agreed-upon list of symptoms. Ten one day as I was going down the list of diseases I knew she did not have, she started to laugh. I had laughed frequently about some of her symptoms, but this was the first time I had heard her laugh. After she collected herself, she said, Okay, this is getting ridiculous. I wanted to ask her ten thousand questions about what she was thinking and how she had arrived at the idea of being ridiculous.

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The possibility of enforcing this will very to define a patient to have control of the asthma order forzest 20 mg fast delivery, if much determine the effectiveness of the FEV1 there are no symptoms and the patient did not use variable in discriminating between treatments generic forzest 20mg without a prescription. The percentage of such days In COPD studies lung function is also of with asthma control can be a useful summary interest, but for this disease the symptomatic measure for some patient populations, typically benefit is stressed more. A variant of this is to define night sleep, breathlessness, coughing and chest mild exacerbations, or episodes, of asthma from tightness seem to be accepted symptoms to diary cards by looking for worsening of lung include in diary cards. The exact criteria for such blockage, rhinorrhea, sneezing and/or itchy nose episodes probably need to be adjusted to the which sometimes are combined into the nasal patient population under study, and to the study index score, which is the sum of them. In order to avoid spurious events, it might addition to this, eye symptoms are recorded as be a good idea to define an event to have occurred a secondary variable. The most readily available for two consecutive days in order to be labelled objective measure in the clinical trial setting is an episode. From an analysis point of view we either the Peak Nasal Inspiratory Flow (PNIF) or can analyse time to first such exacerbation or Peak Nasal Expiratory Index. As already indicated, asthmatic patients, especially PEF, and the dis- in fixed dose studies period mean values are often ease asthma in general. When we interpret diary computed, not only of PEF measurements, but card data, obtained over a longer period, we must RESPIRATORY 373 interpret it on a group mean level. A discussion General health status scales such as the Sick- on individual responders is virtually meaning- ness Impact Profile with 136 items26 have been less. This cannot be tionnaires and single-item measures of health assessed on the basis of diary card data, since has also been proposed. The Nottingham Health the underlying disease is, by definition, vary- Profile with 45 items and SF-36 (a Measures ing – what seems to be a clear response could of Sickness short-form general health survey) well be a period of good asthma control totally are now widely used and validated. The SF-36 unrelated to drug effect (in some cases a study Health Status Questionnaire is based on 36 items effect) and the converse. This is obvious once selected to represent eight health concepts (phys- one has inspected placebo data in a long-term ical, social and role functioning; mental health; study. However this does not exclude that one can health perception; energy/fatigue; patin; and gen- define responders according to some criteria and eral health). This is It is perhaps the most comprehensive question- true irrespective of whether the dose in question naire for evaluation of quality of life in airways refers to the investigational drug or to some diseases and allows for direct numerical compar- concomitant drug (as e. The measure consists of 50 Asthma and COPD are chronic disorders that (76 responses) items that produce three domain can place considerable restrictions on the physi- scores and one overall score. The domains are: cal, emotional and social aspects of the lives of symptoms (severity and frequency), activity (that patients. Quality of life may be use- ful for assessing the degree of morbidity, e. It is assessed by questionnaires that include a large set of phys- HOW TO AVOID BIAS ical and psychological characteristics assessing the general functioning and well-being in the con- Blinding text of lifestyle. That way, at least, the patient does the placebo group, which probably is due to not know whether he gets active drug or not. The classical methods to Open labelled studies might be acceptable for avoid expectation bias, blinding and randomisa- some systemic effects studies where the outcome tion, are therefore important. A clinical study in variable is the plasma concentrations of some this area should follow a double-blind approach marker, or in long-term safety studies. For many The code should not be broken until all deci- outcome variables some prognostic factors are sions concerning data validity have been taken known, and it is important for the credibility of and documented. The observed outcome can still be due say, two different drugs involved, but also two to an imbalance of prognostic factors between different inhalers (or perhaps one drug in two groups, but randomisation at least means that this different inhalers). On each inhalation meaningless to do group comparability testing at occasion, the subject has to inhale not only from baseline. The p-value computed from a statistical the inhaler with active substance, but also from test is a measure of how certain one is that the the other inhalers, but containing placebo. Note that the use of different inhalers obtained before randomisation), say the mean, for implies a consideration on the order in which two treatments, the p-value is a measure of how these should be taken. However, if we trust Rhinitis studies pose a special problem in terms our randomisation procedures, there is no factor of blinding because the double dummy technique that can explain why the two groups should not is not considered appropriate – there is a fear that be equal except for chance alone, so we must additional placebo material may clear the airways conclude that an unlikely event has occurred. This is a problem mainly when two different But the extent of that effect does not depend on drugs inhaled through different devices are to be the p-value of a test at baseline, it depends on the compared. The partial remedy that is most often correlation of the effect variable with the baseline used is to include a placebo group, and let half variable in question. This means that a large RESPIRATORY 375 baseline difference might have no consequences problem, since they should occur with similar at all, or a small difference at baseline might frequency in different groups. In the respiratory area effective treatment is expected to have less con- it is very rare that the latter is the case. As a consequence observed differences at baseline causes concern, there is a bias towards no effect by includ- the robustness of the results should be checked ing those measurements when computing period with respect to this issue, not a separate test means for instance. There seems to be no easy way Another way to risk selection bias, also in a out of this dilemma, and the approach we have randomised, double-blind study, is to exclude taken is to ignore the additional information on data obtained on treatment. To exclude patients recently taken rescue medication for the analy- on data obtained prior to first dose cannot sis, but instead plot, descriptively only, for each in itself produce bias. However the prognostic day the proportion of patients that takes rescue factors for respiratory trials, like FEV in percent close enough to peak flow measurement. Hope- 1 fully, and this is usually the case, the main result of predicted normal and reversibility, are only and this graph gives the same message on effect. Immediate responses that disappear within the protocol a guide to the physician, not the a short period of time.

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