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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Table 16.1: Recombinant

Table 16.1: Recombinant proteins/enzymes licensed in the UK (examples) soluble insulin, a real advance for some patients (see Chapter 37). Other ‘designer’ insulins have longer actions or other kinetic features that are advantageous in specific circumstances. In addition to producing recombinant human hormones (see Table 16.2) and other recombinant proteins (e.g. hirudin, the anticoagulant protein of the leech), recombinant monoclonal antibodies for treating human diseases have been produced originally in immortalized clones of mouse plasma cells. Not surprisingly, the original murine antibodies induced antibody responses in humans which in turn caused disease or neutralizing antibodies, rendering the monoclonal antibodies ineffective if used repeatedly (Table 16.3). Immunoglobulins have been gradually humanized to reduce the risk of an immune response on repeated treatments. In cancer therapy, monoclonal antibodies have been developed against a tumour-associated antigen, e.g. trastuzumab against the HER2 protein (over-expressed in certain breast CELL-BASED AND RECOMBINANT DNA THERAPIES 93 Protein/enzyme Indication Recombinant coagulation factors VIII and VIIa Haemophilia Imiglucerase Gaucher’s disease Interferon alfa Hepatitis B and C, certain lymphomas and solid tumours Interferon beta Multiple sclerosis Epoetin alfa and beta (recombinant human Anaemia of chronic renal failure. To increase erythropoietin) yield of autologous blood, e.g. during cancer chemotherapy Drotrecogin alfa (activated) (recombinant activated protein C which reduces microvascular dysfunction) Severe sepsis Table 16.2: Hormones/hormone antagonists (examples) Mode of action Indication Somatropin Synthetic human Growth hormone growth hormone (hGH) deficiency Pegvisomant Genetically modified hGH that blocks hGH receptors Acromegaly Follitropin Recombinant human Infertility alfa and follicle stimulating beta hormone Insulin aspart, Recombinant human Diabetes (helps glulisine and insulin analogues, glucose control in lispro faster onset of action some patients/ situations) cancers in particular). Most facilitate the body’s immune system in destroying the cancer cells or reduce the blood supply to the tumour. Abciximab (see Chapter 30) inhibits platelet aggregation by blocking the glycoprotein receptor that is a key convergence point in different pathways of platelet aggregation. It is used as an adjunct to heparin and aspirin for the prevention of ischaemic complications in high-risk patients undergoing percutaneous coronary intervention. It is a murine monoclonal antibody and can only be used in an individual patient once. Most recently developed monoclonal antibodies have been fully humanized. In comparison to most conventional ‘small molecule’ drugs, the antibodies’ activities are very specific and toxicity is usually directly related to the targeted effect either through excessive effect or a ‘downstream’ consequence of the effect. The effects are usually very species-specific, so extrapolation from animal studies is more difficult. The initial doses in humans should be a fraction of the minimum anticipated biological effect level (MABEL, see Figure 16.1) taking into account concentration, receptor occupancy, relative potency, likely dose–response curve, and effects of excessive pharmacology rather than just the ‘no observable adverse effect level’ (NOAEL) which is the mainstay of first dose calculation for conventional small molecule drugs. Recombinant techniques have also been of value in the development of vaccines, thereby avoiding the use of intact virus. Suspensions of hepatitis B surface antigen prepared from yeast cells by recombinant DNA techniques are already widely used to prevent hepatitis B infection in high-risk groups in the UK. In comparison to traditional egg-based and cell-based vaccines, DNA vaccines using plasmid DNA coding for specific epitopes of influenza virus may be developed, manufactured and distributed much more rapidly and effectively. With the current likelihood of an influenza pandemic caused by a new strain of virus predicted by the World Health Organization (WHO), the ability to produce such DNA vaccines may save millions of lives.

94 CELL-BASED AND RECOMBINANT DNA THERAPIES Table 16.3: Licensed monoclonal antibodies (examples) Monoclonal antibody Mode of action Indication Abciximab Inhibits glycoprotein IIb/IIIa, platelet aggregation Angioplasty Omalizumab Anti-IgE Prophylaxis of severe allergic asthma Infliximab, Adalimumab Anti-TNFα Rheumatoid arthritis, psoriatic arthritis Basiliximab, Daclizumab Bind to IL-2Rα receptor on T cells, prevent Prophylaxis of acute rejection in T-cell proliferation, causing immunosuppression allogenic renal transplantation Bevacizumab (Avastin®) Inhibits vascular endothelial growth factor (VEGF), hence inhibits angiogenesis Metastatic colorectal cancer Pegaptanib and ranibizumab lnhibit VEGF Neovascular age-related macular degeneration Effect 100 MABEL 80 60 40 20 GENE THERAPY Therapeutic range Unacceptable toxicity 0 10 100 1000 10000 Dose or exposure Figure 16.1: Explanation of minimum anticipated biological effect level (MABEL) (kindly provided by P Lloyd, Novartis, Basel, Switzerland). Unbroken line, desired effect; dashed line, undesired effect. The increasing potential to exploit advances in genetics and biotechnology raises the possibility of prevention by gene therapy both of some relatively common diseases which are currently reliant on symptomatic drug therapy, and of genetic disorders for which there is currently no satisfactory treatment, let alone cure. Gene therapy is the deliberate insertion of genes into human cells for therapeutic purposes. Potentially, gene therapy may involve the deliberate modification of the genetic material of either somatic or germ-line cells. Germ-line genotherapy by the introduction of a normal gene and/or deletion of the abnormal gene in germ cells (sperm, egg or zygote) has the potential to correct the genetic defect in many devastating inherited diseases and to be subsequently transmitted in Mendelian fashion from one generation to the next. Table 16.4: Prevalence of some genetic disorders which result from a defect in a single gene Disorder Estimated prevalence Familial hypercholesterolaemia 1 in 500 Polycystic kidney disease 1 in 1250 Cystic fibrosis 1 in 2000 Huntington’s chorea 1 in 2500 Hereditary spherocytosis 1 in 5000 Duchenne muscular dystrophy 1 in 7000 Haemophilia 1 in 10 000 Phenylketonuria 1 in 12 000 The prevalence figures for inherited diseases in which a single gene is the major factor are listed in Table 16.4. However, germ-line gene therapy is prohibited at present because of the unknown possible consequences and hazards, not only to the individual but also to future generations. Thus, currently, gene therapy only involves the introduction of genes into human somatic cells. Whereas gene therapy research was initially mainly directed at single-gene disorders, most of the research currently in progress is on malignant disease. Gene therapy trials in cancer usually involve destruction of tumour cells by the insertion of a gene that causes protein expression that induces an immune response against those cells, or by the introduction of ‘suicide genes’ into tumour cells. Cystic fibrosis (CF) is the most common life-shortening autosomal-recessive disease in Europeans. It is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Over 600 different CF mutations have been recognized, although one mutation (F508) is present on over 70% of CF chromosomes. Phase I studies using adenoviral or liposomal vectors to deliver the normal CFTR gene to the airway epithelium have shown that gene transfer is feasible, but with current methods is only transient in

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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

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    DIGOXIN Myxoedematous patients are

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    ● Introduction 41 ● Role of dru

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  • 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
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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 150 and 151: FURTHER ANTI-EPILEPTICS Other drugs
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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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