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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Too many statistical

Too many statistical comparisons performed differences should be reported as confidence intervals (usually 95% confidence intervals). Such intervals will diminish as the sample size is increased. Confidence intervals reflect the effects of sampling variability on the precision of a procedure, and it is important to quote them when a ‘non-significant’ result is obtained, and when comparing different estimates of effectiveness (e.g. drug A in one trial may have performed twice as well as placebo, whereas drug B in another trial may have performed only 1.5 times as well as placebo; whether drug A is probably superior to drug B will be apparent from inspection of the two sets of confidence intervals). If many parameters are analysed, some apparently ‘significant’ differences will be identified by chance. For example, if 100 parameters are analysed in a comparison of two treatments, one would expect to see a ‘significant’ difference in approximately five of those parameters. It is therefore very important to prespecify the primary trial end-point and secondary end-points that will be analysed. Statistical corrections can be applied to allow for the number of comparisons made. One must also consider the clinical importance of any statistically significant result. For example, a drug may cause a statistically significant decrease in blood pressure in a study, but if it is only 0.2 mmHg it is not of any clinical relevance. CLINICAL DRUG DEVELOPMENT For most new drugs, the development process – following a satisfactory preclinical safety evaluation – proceeds through four distinct phases. These are summarized below. Figure 15.3 illustrates the overall decision-making process for determining whether or not a new therapy will be clinically useful. PHASE I TYPE I ERROR False-positive result (significant difference found when no difference present) Too small sample size (insufficient power) Figure 15.2: Different types of statistical error. TYPE II ERROR False-negative result (no significant difference found when difference present) The initial studies of drugs in humans usually involve healthy male volunteers unless toxicity is predictable (e.g. cytotoxic agents, murine monoclonal antibodies). The first dose to be administered to humans is usually a fraction of the dose that produced any effect in the most sensitive animal species tested. Subjective adverse events, clinical signs, haematology, biochemistry, urinalysis and electrocardiography are used to assess tolerability. Depending on the preclinical data, further, more specific evaluations may be appropriate. The studies are placebo controlled to reduce the influence of environment and normal variability. If the dose is well tolerated, a higher dose will be administered either to a different subject in a parallel CLINICAL DRUG DEVELOPMENT 89 design, or to the same group in an incremented crossover design. This process is repeated until some predefined end-point such as a particular plasma concentration, a pharmacodynamic effect or maximum tolerated dose is reached. Data from the single-dose study will determine appropriate doses and dose intervals for subsequent multiple-dose studies. If the drug is administered by mouth, a food interaction study should be conducted before multiple-dose studies. The multiple-dose study provides further opportunity for pharmacodynamic assessments, which may demonstrate a desired pharmacological effect and are often crucial for the selection of doses for phase II. Having established the dose range that is well tolerated by healthy subjects, and in some cases identified doses that produce the desired pharmacological effect, the phase II studies are initiated. Key points Phase I studies: • initial exposure of humans to investigational drug; • assessment of tolerance, pharmacokinetics and pharmacodynamics in healthy subjects or patients; • usually healthy male volunteers; • usually single site; • 40–100 subjects in total. PHASE II Phase II studies are usually conducted in a small number of patients by specialists in the appropriate area to explore efficacy, tolerance and the dose–response relationship. If it is ethical and practicable, a double-blind design is used, employing either a placebo control or a standard reference drug therapy as control. These are the first studies in the target population, and it is possible that drug effects, including adverse drug reactions and pharmacokinetics, may be different to those observed in the healthy subjects. If the exploratory phase II studies are promising, larger phase III studies are instigated, using a dosage regimen defined on the basis of the phase II studies. Key points Phase II studies: • initial assessment of tolerance in ‘target’ population; • initial assessment of efficacy; • identification of doses for phase III studies; • well controlled with a narrowly defined patient population; • 100–300 patients in total; • usually double-blind, randomized and controlled. PHASE III Phase III is the phase of large-scale formal clinical trials in which the efficacy and tolerability of the new drug is established.

90 INTRODUCTION OF NEW DRUGS AND CLINICAL TRIALS Does the therapy have unacceptable adverse effects? No Does the therapy exhibit potentially useful clinical effects? Yes Are the benefits statistically significant over existing therapy/placebos in well-designed clinical trials? Yes Yes Are these benefits of useful magnitude? Useful Patient groups who respond more or less well may be identified, patient exposure (both numbers and duration of therapy) is increased, and less common type B (see Chapter 12) adverse reactions may be identified. During this period, the manufacturers will be setting up plant for large-scale manufacture and undertaking further pharmaceutical studies on drug formulation, bioavailability and stability. The medical advisers to the company, in association with their pharmacological, pharmaceutical and legal colleagues, will begin to collate the large amount of data necessary to make formal application to the MHRA or EMEA for a product licence. Marketing approval may be general or granted subject to certain limitations which may include restriction to hospital practice only, restriction in indications for use, or a requirement to monitor some particular action or organ function in a specified number of patients. Doctors are reminded (by means of a black triangle symbol beside its entry in the British National Formulary) that this is a recently introduced drug, and that any suspected adverse reaction should be reported to the MHRA or Commission on Human Medicines. Key points Phase III studies: • confirmation of effective doses; • expanded tolerability profile; • collection of data on a more varied patient population with indication; • data on overall benefit/risk; • can be placebo or more usually active controls; • multicentre; • commonly 1000–5000 patients in total; • usually double-blind. PHASE IV Phase IV studies are prospective trials performed after marketing approval (the granting of a product licence). These may assess the drug’s clinical effectiveness in a wider population No No No Yes Not useful Figure 15.3: Flow chart for deciding usefulness of a new therapy. and may also help in the detection of previously unrecognized adverse events (see Chapter 12). Key points Phase IV studies: • performed after marketing approval and related to the approved indications; • exposure of drug to a wider population; • different formulations, dosages, duration of treatment, drug interactions and other drug comparisons are studied; • detection and definition of previously unknown or inadequately quantified adverse events and related risk factors. POSTMARKETING SURVEILLANCE The MHRA closely monitors newly licensed drugs for adverse events through the yellow card reporting system (see Chapter 12). Direct reporting by patients of adverse events was introduced in 2004. SAMM (Safety Assessment of Marketed Medicines) studies may be initiated which can involve many thousands of patients. GENERIC DRUGS Once the patent life of a drug has expired, anyone may manufacture and sell their version of that drug. The generic drug producer does not have to perform any of the research and development process other than to demonstrate that their version of the drug is ‘bioequivalent’ to the standard formulation. The convention accepted for such ‘bioequivalence’ is generous, and the issue is the subject of current debate by biostatisticians. In practice, the essential point is that clinically untoward consequences should not ensue if one preparation is substituted for the other.

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    A Textbook of Clinical Pharmacology

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    A Textbook of Clinical Pharmacology

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    This fifth edition is dedicated to

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    FOREWORD viii PREFACE ix ACKNOWLEDG

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    PREFACE Clinical pharmacology is th

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    PART I GENERAL PRINCIPLES

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    ● Use of drugs 3 ● Adverse effe

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    and acquired factors, notably disea

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    100 Effect (%) 0 0 5 10 1 10 100 (a

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    Dose ratio -1 100 50 The relationsh

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    ● Introduction 11 ● Constant-ra

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    In reality, processes of eliminatio

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    lood (from which samples are taken

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    ● Introduction 17 ● Bioavailabi

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    ROUTES OF ADMINISTRATION ORAL ROUTE

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    Transdermal absorption is sufficien

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    FURTHER READING Fix JA. Strategies

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    and thromboxanes are CYP450 enzymes

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    and lorazepam. Some patients inheri

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    Orally administered drug Parenteral

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    ● Introduction 31 ● Glomerular

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    ACTIVE TUBULAR REABSORPTION This is

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    DISTRIBUTION Drug distribution is a

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    Detailed recommendations on dosage

  • Page 50 and 51: DIGOXIN Myxoedematous patients are
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  • Page 58 and 59: vagina in girls in their late teens
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  • Page 62 and 63: Case history A 20-year-old female m
  • Page 64 and 65: METABOLISM At birth, the hepatic mi
  • Page 66 and 67: lifelong effects as a result of tox
  • Page 68 and 69: DISTRIBUTION Ageing is associated w
  • Page 70 and 71: DIGOXIN Digoxin toxicity is common
  • Page 72 and 73: FURTHER READING Dhesi JK, Allain TJ
  • Page 74 and 75: Factors involved in the aetiology o
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  • Page 80 and 81: predisposes to non-immune haemolysi
  • Page 82 and 83: ● Introduction 71 ● Useful inte
  • Page 84 and 85: Response Therapeutic range Toxic ra
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  • Page 96 and 97: Key points • Genetic differences
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  • Page 110 and 111: A case report has suggested a possi
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  • Page 114 and 115: PART II THE NERVOUS SYSTEM
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  • Page 120 and 121: Key points • Insomnia and anxiety
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  • Page 132 and 133: Key points Drug treatment of depres
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    FURTHER ANTI-EPILEPTICS Other drugs

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    Case history A 24-year-old woman wh

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    Assessment of migraine severity and

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    ● General anaesthetics 145 ● In

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    is the theoretical concern of a ‘

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    • Respiratory system - apnoea fol

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    Competitive antagonists (vecuronium

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    have also proved useful in combinat

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    ● Introduction 155 ● Pathophysi

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    ASPIRIN (ACETYLSALICYLATE) Use Anti

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    Key points Drugs for mild pain •

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    increases, correlating with the hig

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    • If possible, use oral medicatio

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    PART III THE MUSCULOSKELETAL SYSTEM

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    ● Introduction: inflammation 167

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    Chapter 33). All NSAIDs cause wheez

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    • Stomatitis suggests the possibi

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    Pharmacokinetics Allopurinol is wel

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    PART IV THE CARDIOVASCULAR SYSTEM

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    ● Introduction 177 ● Pathophysi

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    esponsible for the strong predilect

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    Ezetimibe Fat Muscle Dietary fat In

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    educed). The risk of muscle damage

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    ● Introduction 185 ● Pathophysi

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    Each of these classes of drug reduc

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    AT 1 receptor) produce good 24-hour

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    Table 28.2: Examples of calcium-cha

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    Key points Drugs used in essential

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    Case history A 72-year-old woman se

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    Assess risk factors Investigations:

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    Persistent ST segment elevation Thr

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    Mechanism of action GTN works by re

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    Because of the risks of haemorrhage

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    Intrinsic pathway XIIa XIa the acti

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    that the pharmacodynamic response i

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    used with apparent benefit in acute

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    ● Introduction 211 ● Pathophysi

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    The drugs that are most effective i

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    therapeutic plasma concentration ca

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    ● Common dysrhythmias 217 ● Gen

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    BASIC LIFE SUPPORT CARDIOPULMONARY

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    arrest. The electrocardiogram is li

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    should be given to insertion of an

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    Drug interactions Amiodarone potent

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    effect when treating sinus bradycar

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    Case history A 24-year-old medical

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    PART V THE RESPIRATORY SYSTEM

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    CHAPTER 33 THERAPY OF ASTHMA, CHRON

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    STEP 5: CONTINUOUS OR FREQUENT USE

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    Adenylyl cyclase Table 33.1: Compar

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    Drug interactions Although synergis

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    use in asthma has declined consider

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    α 1-antitrypsin deficiency, neutro

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    PART VI THE ALIMENTARY SYSTEM

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    ● Peptic ulceration 247 ● Oesop

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    PEPTIC ULCERATION 249 • With rega

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    Ranitidine has a similar profile of

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    Vestibular stimulation ? via cerebe

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    cortical centres affecting vomiting

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    • in hepatocellular failure to re

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    Ciprofloxacin is occasionally used

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    withdrawal), small doses of benzodi

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    Table 34.7: Dose-independent hepato

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    ● Introduction 265 ● General ph

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    dinucleotide (NAD) and nicotinamide

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    Table 35.1: Common trace element de

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    PART VII FLUIDS AND ELECTROLYTES

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    ● Introduction 273 ● Volume ove

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    Key points Diuretics Diuretics are

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    is sometimes caused by drugs, notab

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    or with potassium-sparing diuretics

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    Greger R, Lang F, Sebekova, Heidlan

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    PART VIII THE ENDOCRINE SYSTEM

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    ● Introduction 285 ● Pathophysi

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    in prefilled injection devices (‘

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    Metformin should be withdrawn and i

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    FURTHER READING American Diabetes A

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    deficiency. Potassium iodide (3 mg

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    fertility. It is contraindicated du

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    ● Introduction 297 ● Vitamin D

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    effective in life-threatening hyper

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    Further reading Block GA, Martin KJ

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    Table 40.1: Actions of cortisol and

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    injection may be useful, but if don

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    CHAPTER 41 REPRODUCTIVE ENDOCRINOLO

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    elease by the pituitary via negativ

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    Treatment with depot progestogen in

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    infusion using an infusion pump to

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    significant proportion of men who r

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    with symptoms caused by the release

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    FURTHER READING Birnbaumer M. Vasop

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    PART IX SELECTIVE TOXICITY

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    ● Principles of antibacterial che

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    2. transfer of resistance between o

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    Pharmacokinetics Absorption of thes

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    Mechanism of action Macrolides bind

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    asic quinolone structure dramatical

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    Case history A 70-year-old man with

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    PRINCIPLES OF MANAGEMENT OF MYCOBAC

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    Pharmacokinetics Absorption from th

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    MYCOBACTERIUM LEPRAE INFECTION Lepr

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    POLYENES AMPHOTERICIN B Uses Amphot

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    therapy is adequate though more fre

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    NUCLEOSIDE ANALOGUES ACICLOVIR Uses

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    Table 45.3: Summary of available ac

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    Uses Interferon-α when combined wi

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    ● Introduction 351 ● Immunopath

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    Table 46.1: Examples of combination

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    NON-NUCLEOSIDE ANALOGUE REVERSE TRA

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    FUSION INHIBITORS Uses Currently, e

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    salvage therapy include azithromyci

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    ● Malaria 361 ● Trypanosomal in

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    Pharmacokinetics Chloroquine is rap

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    Table 47.2: Drug therapy of non-mal

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    ● Introduction 367 ● Pathophysi

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    Table 48.1: Classification of commo

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    Polymorph count/mm 3 (a) (b) 10 000

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    doses are used to prepare patients

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    Adverse effects Methotrexate Inhibi

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    Table 48.7: Summary of clinical pha

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    Table 48.9: Summary of the clinical

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    Plasma membrane Signal transduction

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    Table 48.10: Monoclonal antibodies

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    INTERFERON-ALFA 2B Interferon-alfa

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    PART X HAEMATOLOGY

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    ● Haematinics - iron, vitamin B 1

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    one marrow to produce red cells. Th

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    EPO Erythroid precursors Erythrocyt

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    Therapeutic principles The extent o

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    PART XI IMMUNOPHARMACOLOGY

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    ● Introduction 399 ● Immunity a

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    Key points Antigen recognition Expr

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    Table 50.1: Novel anti-proliferativ

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    Key points Treatment of anaphylacti

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    DRUGS THAT ENHANCE IMMUNE SYSTEM FU

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    PART XII THE SKIN

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    ● Introduction 411 ● Acne 411

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    DERMATITIS (ECZEMA) PRINCIPLES OF T

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    SPECIALISTS ONLY SPECIALISTS ONLY E

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    TREATMENT OF OTHER SKIN INFECTIONS

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    effect of too high a dose of UVB in

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    PART XIII THE EYE

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    ● Introduction: ocular anatomy, p

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    to cause pupillary dilatation, name

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    Table 52.3: Antibacterial agents us

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    Table 52.6: Common drug-induced pro

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    PART XIV CLINICAL TOXICOLOGY

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    ● Introduction 433 ● Pathophysi

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    Table 53.2: Central nervous system

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    which provide anonymized data to th

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    Peak plasma levels after smoking ci

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    Key points Acute effects of alcohol

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    FURTHER READING Goldman D, Oroszi G

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    Table 54.2: Common indications for

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    Table 54.5: Antidotes and other spe

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    Commission on Human Medicines (CHM)

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    Note: Page numbers in italics refer

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    atrial fibrillation 217, 221 digoxi

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    Cushing’s syndrome 302 cyclic ade

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    5-fluorouracil 375-6 fluoxetine, mo

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    children 54 diazepam 108 iron prepa

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    non-steroidal anti-inflammatory dru

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    puberty (male), delay 314 puerperiu

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    tolerance 9, 433 benzodiazepines 10

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