Missouri Tech. O. Curtis, MD: "Buy cheap Claritin online - Trusted Claritin OTC".
A carotid cavernous fistula deserves mention in this Common benign tumors of the orbit further include hem- section because it can present with proptosis buy cheap claritin 10mg line allergy forecast delaware. Capillary hemangiomas are seen ophthalmic vein best claritin 10 mg allergy medicine is not working, which can be accompanied by enlarge- in infants in the first year of life discount claritin 10mg overnight delivery allergy medicine name brand, most commonly located ment of the extraocular muscles order claritin 10mg mastercard allergy forecast paris france. They typically grow rapidly orbit are rare, most common in the intraconal space and, for 1 to 2 years, regress over 3 to 5 years, and completely on imaging, are sharply marginated and oval or fusiform regress by late childhood (with proliferative, involuting, in shape. Most tumors of the lacrimal most common intraconal vascular orbital tumor in adults, gland are benign, with benign mixed tumor (previously is seen most often in the second to fourth decades and termed pleomorphic adenoma) most common. It is a appears as a well-defined, smoothly marginated, homog- well-encapsulated round lesion often producing scalloped enous mass. The most common ma- angiomas typically manifest patchy, central enhancement lignant lacrimal gland tumor is adenoid cystic carcinoma. A lym- Lymphoma of the lacrimal gland may also be encountered, phatic malformation is an unencapsulated mass seen in unilateral or bilateral, typically B-cell lymphoma. In the first patient, the posterior portion of the optic nerve within the orbit is slightly prominent, with dis- tinctive “tram track” calcification. In the second patient, linear calcification and abnormal enhancement are demon- strated along the optic nerve sheath within the orbit, with extension of this meningioma along the nerve through the optic canal to involve the dura intracranially (arrow). Fat-containing dermoid tumors will manifest high signal intensity on T1-weighted images, with the signal suppressed on fat-saturated, postcontrast scans. The uvea is the middle layer, is vascular in nature (providing the vascular supply to the eye), and contains the iris, ciliary body, and choroid. The retina is the innermost layer, separated from the vitreous by the hyaloid membrane. The retina has two layers, the inner being the complex sensory layer and the outer being the retinal pigment epithelium. There are three potential spaces and, thus, three types of retinal detachment: that between hyaloid and sensory retina (the posterior hyaloid space), that between the sensory retina and retinal pigment epithelium (the sub- retinal space), and that between the choroid and the sclera (the suprachoroidal space). In the first, on an axial scan, a large intraconal enhancing mass is is seen in adults 50 years of age, with macular degen- noted circumferential to the optic nerve, with prominent proptosis. Separation of the sensory retina from retinal pig- In the second, a small meningioma is visualized on a coronal image, ment epithelium produces the classic V-shape imaging with abnormal enhancing soft tissue (arrow) surrounding the optic appearance (of a retinal detachment), with convergence nerve within the posterior orbit. Choroidal detachment can be due to surgery, trauma, or inflamma- most common location is the superior temporal quadrant tory disease, with the fluid either serous or hemorrhagic of the orbit, adjacent to the frontozygomatic suture (with in nature. A well-defined, smoothly marginated mass is identified in the intraconal space, the most common location for this tumor. Note also the patchy enhancement on the axial postcontrast scan, that “fills-in” on the delayed sagittal scan. The globe is compressed and together with sagittal T2- and coronal postcontrast fat sat T1- deformed, and the orbit expanded. Although there is a small solid weighted (part 2) scans are presented in this 2-year-old child. A large, component, the lesion is predominantly cystic with prominent en- lobulated, multilocular, trans-spatial orbital mass is noted, which is hancement postcontrast of the cyst margins Retinoblastoma is the most common childhood intra- retrobulbar spread, optic nerve invasion, and intracranial ocular tumor (98% of cases present before 6 months of metastases. It is bilateral in 25 a variety of benign mass lesions can mimic retinoblas- to 30%. The entity trilateral/quadrilateral retinoblas- more than 90% of retinoblastomas, in marked distinction toma refers to a patient with bilateral retinoblastomas to other intraocular lesions. The band is placed around the equator of the globe, with compression promoting apposition of the choroid and sclera to the retina. A lentiform fluid collection is noted mound-shaped with a broad choroidal base (Fig. There are many uncommon, benign diseases that occur in the globe, some of which can mimic retinoblastoma, which are be- ■ Visual Pathway yond the scope of this textbook. These include persistent hyperplastic primary vitreous, Norrie disease, Warburg At the optic chiasm, the axons from the nasal half of the syndrome, retinopathy of prematurity, Coats disease, and retina cross to the contralateral optic tract. Ocular choroidal melanoma and choroidal metastases Thus, in terms of visual fields, the right side (present on (Fig. Ocular melanoma is the the left retina) projects to the left hemisphere (optic tract, most common primary intraocular neoplasm in adults, lateral geniculate ganglion [located in the thalamus], optic typically unilateral, with retinal detachment frequent. An optic plays a limited role for characterization and definition of nerve lesion leads to monocular blindness. Presence or development of an intracranial lesion defines a trilateral retinoblastoma, with the majority of such lesions noted in the pineal region. These patients carry a poorer prognosis, with lower survival and a propensity to leptomeningeal tumor spread. As discussed in the brain section, pituitary macroadenomas can extend superiorly, splaying and compressing the optic chiasm, leading to bitemporal hemianopsia. An ophthalmic artery aneurysm is the most common aneurysm to cause visual symptoms, due to impingement on the visual pathway. Ischemia—for example, due to reti- nal or ophthalmic artery emboli—can lead to transient loss of vision in one eye (monocular blindness). Ischemia in- volving the visual cortex (occipital lobe) will lead to con- tralateral homonymous hemianopsia. Optic neuritis can cause either complete or partial loss of vision in one eye, with the most common etiology being multiple sclerosis. Retinoblastomas can have similar signal intensity characteristics to melanoma due to hemorrhage, necrotic ■ Paranasal Sinuses, Nasal Cavity, and Face elements, or calcification therein. On the T2-weighted axial image, this large retinoblas- plate and the floor by the hard palate. Although not cosa is found in the upper portion of the nasal cavity, shown, it also was slightly hyperintense on the T1-weighted image. Fat saturation by the ethmoid bone posteriorly, cartilage anteriorly, and is routinely used for postcontrast imaging in the orbits, suppress- the vomer posteroinferiorly. The turbinates (nasal con- ing the signal intensity from retrobulbar fat that might otherwise cha), of which there are three (inferior, middle, and supe- obscure findings. For retinoblastoma, specifically, evaluation for rior), lie along the lateral walls of the nasal cavity, with a possible optic nerve enhancement is important, with the latter in- space (meatus) beneath each turbinate, named according dicative of contiguous tumor spread. The semilunar hiatus is a crescent-shaped groove in the middle meatus, with the in the outer halves of both eyes), and an optic tract lesion ostium for the maxillary sinus located posteriorly therein. There is a normal Any portion of the visual pathway can be involved by an nasal cycle, with alternating partial congestion and decon- optic glioma, as previously noted. Involvement of the optic gestion of the nasal turbinates with time, from the left side Fig. This 70-year-old patient pre- sented to her ophthalmologist with painless loss of vision in the left eye.
When separation changed only if they become dislodged or wound fuid escapes occurs buy claritin 10 mg with mastercard allergy symptoms to nuts, it can be excised generic 10mg claritin visa allergy symptoms headache fatigue. Periulcer skin must be kept dry not only to avoid maceration Underlying contributing factors but also to permit the dressing to adhere to the skin cheap 10 mg claritin otc allergy testing grand rapids. To obliterate dead space claritin 10mg low cost allergy testing honolulu, fll deep ulcers loosely with a hydrocolloid, Management of anemia, malnutrition, diabetes mellitus, hydra- a hydrogel wound fller, or an alginate rope before applying a tion, and incontinence is essential. This same material should be placed under ing approximately 30–35 calories/kg daily and 1. Ascorbic acid 500 mg twice daily may enhance healing, after serial surgical debridement can often be controlled with but this has not been proven. Keep in mind that the patient who an alginate dressing; the calcium alginate assists in the clotting is debilitated and has a multitude of other conditions may have pathway. Moistening with saline can loosen an alginate dress- no healing capabilities (skin failure). Increased bacterial burden may impede healing before Obtain total protein, serum albumin clinical signs of infection become apparent. The odor of an Obtain complete blood count infected ulcer can often be eliminated by applying metronida- zole gel to the ulcer bed. Systemic antimicrobial agents are indi- Clinical observation is the key to making the diagnosis. Cuta- cated for patients with bacteremia, sepsis, advancing cellulitis, neous biopsies will not be helpful, although biopsies for aerobic or osteomyelitis. Patients at risk need to be considered in terms of the underly- Blanchable erythema and non-blanchable erythema ing disease process: Spinal cord injury in an otherwise healthy person Blanchable and non-blanchable erythema represent the initial Neurologic disease with no medical disease, but a devastating development of the decubitus ulcer. The early lesions of non- condition such as multiple sclerosis or a cerebral vascular acci- blanchable erythema are bright red; later, they become dark red dent compromising the body integrity to purple. Both can be treated with adherent synthetic dressings to Debilitation with a multitude of medical diseases affecting the protect the lesion from friction and shear, topical corticosteroids, or patient (e. The bright red lesion can also be treated with 2% disease, Alzheimer’s disease, malignancy, malnutrition, and nitroglycerin ointment; 0. Bear in mind that ulcer staging is arbi- emia, serum albumin depletion, anemia, and hypotension. Risk factors associated with pressure ulcer development in critically ill traumatic spinal cord injury patients. Dermatologic observation Wilczweski P, Grimm D, Gianakis A, Gill B, Sarver W, McNett M. Blanchable erythema Clinical variables associated with pressure ulcers were fecal Non-blanchable erythema management systems, incontinence, acidosis, support surfaces, Decubitus dermatitis steroids, and additional equipment with hypotension as the Superfcial ulcer strongest predictor of pressure ulcers in 94 spinal cord injury Deep ulcer patients. Staging Pressure ulcer tissue histology: an appraisal of current Stages are as follows: knowledge. Ostomy Wound Manage 2007; 53: Stage I: non-blanchable erythema of intact skin 40–9. The concept of staging need not be thought of as National Pressure Ulcer Advisory Panel. Results of the national pressure Accumulating evidence suggests that a number of ulcers (most ulcer advisory panel consensus conference. Ostomy Wound Manage 2011; 57: compartment and progress outward to the dermis and epidermis 24–37. In a consensus conference that involved 24 stakeholder organi- By eliminating the current numerical classifcation system and zations from various disciplines, it was unanimously agreed that documenting the partial-thickness and full-thickness depth along pressure ulcers are largely preventable but not always avoidable. Ann value for predicting pressure ulcers in acutely ill veterans than Intern Med 1986; 105: 337–42. Hypoalbuminemia, fecal incontinence, and fractures may iden- tify bedridden patients at greatest risk for developing pressure ulcers. Elimination of pressure C All 40 patients with sacral pressure ulcers showed mild-to- Pressure-reducing and -relieving devices C moderate anemia with low serum iron and normal or increased Removal of necrotic debris C ferritin and hypoproteinemia with albuminemia. Patients who developed fewer pressure sores were those who Dilemmas about the decubitus ulcer: skin-fold ulcerations were turned every 2 to 3 hours. Shearing force as a factor in decubitus ulcers in paraple- Decubitus ulcers continue to have an uncertain etiology. No conclusive evidence on the effects of pressure-relieving Drawsheets for prevention of decubitus ulcer. Decubitus prophylaxis: a prospective trial on the eff- Debridement ciency of alternating-pressure air mattresses and water Collagenase in the treatment of dermal and decubitus mattresses. The incidence of pressure ulcers in patients cared for on the Enzymes can be used alone or in combination with other hospital mattress was signifcantly greater than in patients on forms of debridement. Weight shifting is an effective means of reducing the risk of pressure ulcer formation. J Am Coll Emerg Phys 1976; 5: the supersoft 3-piece mattress on areas of maximum 17–21. Enzymes normally present in wound fuid digest devitalized Mechanical loading and support surfaces. In: Agency for tissue when allowed to collect under a synthetic dressing for Health Care Policy and Research. Debridement of cutaneous ulcer: medical and surgical An overview of pressure-relieving devices. A clinical comparison of two pressure reducing surfaces Debridement can be accomplished by cold steel cutting, by in the management of pressure ulcers. Decubitus chemical application, or by autohemolytic destruction under an 1992; 5: 52–5, 58–60, 62–4. Adv A randomized trial of low-air-loss beds for treatment of Wound Care 1995; 6: 22–44. Patients with pressure ulcers showed a signifcantly improved More effective removal of debris can be accomplished by twice- healing rate. Comparison of total body tissue interface pressure of Maggot debridement therapy of infected ulcers: patient specialized pressure-relieving mattresses. Anderson was not so useful for the elderly who had septic arthritis, chronic C, Rappl L. Evidence to support debridement in enhancing healing is Although vitamins A, B, and C, proteins, and minerals such as scarce, and there are insuffcient data to support debridement zinc and copper promote healing in animal models, supplements for venous ulcers and pressure ulcers. The potential benefts of tube feeding may be lost due to diarrhea, bowel incontinence, and restricted mobility. Topical metronidazole gel: the bacteriology of decubitus A comparison of the effcacy and cost-effectiveness of two ulcers. Clin Dermatol The presence of increasing pain may make infection of a 2007; 25: 33–8. Further evidence is required to deter- There are many occlusive dressings available which are impor- mine which, if any, type of quantitative swab culture is most tant for accelerating wound healing. There are no satisfactory studies available to prove that hyper- High protein with increased caloric contents may enhance baric oxygen is useful in decubitus or arterial ulcers. Langer G, Schloemer G, Knerr A, Kuss O, Pros and cons of various dressing materials, including vacuum- Behrens J.
Back pain is in the lateral radiographic view and close to the mid- another common side efect of a celiac plexus block buy claritin 10mg online allergy testing devices. Indications aorta at a level between the celiac and superior mes- Lumbar sympathetic block may be indicated for enteric arteries buy discount claritin 10mg on-line allergy symptoms every morning. The lumbar sympathetic chain ganglia The most common complication is postural hypo- are in a more anteromedial position to the vertebral tension claritin 10 mg visa allergy symptoms of flu, from block of the visceral sympathetic bodies than the thoracic ganglia generic 10 mg claritin allergy medicine post nasal drip, and are anterior innervation and resultant vasodilation. The lumbar chain is son, patients should be adequately hydrated intrave- usually posterior to the vena cava on the right but is nously prior to this block. The supe- 7 cm 10 cm rior hypogastric plexus usually lies just to the lef of the midline at the L5 vertebral body and beneath the bifurcation of the aorta. The fbers of this plexus divide into lef and right branches and descend to the pelvic organs via the lef and right inferior hypo- L2 gastric and pelvic plexuses. The inferior hypogastric plexus additionally receives preganglionic parasym- pathetic fbers from the S2–S4 spinal nerve roots. Technique Inferior vena cava The patient is positioned prone, and a 15-cm needle Sympathetic ganglia is inserted approximately 7 cm lateral to the L4–L5 spinal interspace. Technique vertebral disc between L5 and S1 and within 1 cm A single-needle technique at the L3 level on either of the vertebral bodies in the anteroposterior view. The nous process and is directed above or just lateral to superior hypogastric plexus block may also be per- the transverse process of the vertebrae (depending formed using a transdiscal approach, though there is on the distance from the midline). Complications include intravascular injection into the vena cava, aorta, or lumbar vessels and somatic Ganglion Impar Block nerve block of the lumbar plexus. Indications Ganglion impar block is efective for patients 21 Superior Hypogastric Plexus Block with visceral or sympathetically maintained pain in the perineal area. Anatomy from the pelvis and is unresponsive to lumbar or The ganglion impar (ganglion of Walther) is the caudal epidural blocks. The two tains visceral sensory fbers that bypass the lower lowest pelvic sympathetic ganglia ofen fuse form- spinal cord. Tis block is usually appropriate for ing one ganglion in the midline just anterior to the patients with cancer of the cervix, uterus, bladder, coccyx. Tis procedure can be facilitated with given within 2 weeks of pain onset but appear to be fuoroscopy or ultrasound. Radiofrequency ablation, of little beneft in the absence of neural compres- or in some cases a neurolytic injection, may provide sion or irritation. Long-term studies have failed to longer duration of analgesia for this sympathetically show any persistent beneft afer 3 months, and these mediated pain. Complications The two most commonly used agents are meth- Intravascular injection and transient bowel or blad- ylprednisolone acetate (40–80 mg) and triamcino- der dysfunction are possible. Dexamethasone is being involve placement of the needle through the ano- used with increased frequency due to its smaller coccygeal ligament, although these may have higher particulate size (smaller than an erythrocyte). Intravascular injection of steroid suspension with larger particulate size may lead to embolic compli- Intravenous Regional Block cations. The steroid may be injected with diluent A Bier block (see Chapter 46) utilizing local anes- (saline) or local anesthetic in volumes of 6–10 mL or thetic solution with or without adjuvants can be 10–20 mL for lumbar and caudal injections, respec- used to interrupt sympathetic innervation to an tively. Injection of on the extremity, which is then elevated and exsan- local anesthetic along with the steroid can be help- guinated using an Esmarch bandage. The tourniquet ful if the patient has signifcant muscle spasm, but it is infated to a pressure that is two times the systolic is associated with risks of intrathecal, subdural, and blood pressure, the Esmarch bandage is removed, intravascular injection. The presenting pain is ofen and the limb is checked to be certain the pulse is transiently intensifed following injection, and the absent and there is no evidence of blood fow. The local anesthetic provides immediate pain relief until solution is then injected and usually lef in place the steroidal antiinfammatory efects take place, for at least 30 min, afer which the tourniquet is usually within 12–48 h. Premature release of the tourniquet may result in a single injection is given if complete pain relief is seizure, hypotension, arrhythmia, edema, diarrhea, achieved. Intravenous regional sympathetic block a second injection may be given 2–4 weeks later. Most pain practitioners utilize fuoroscopy for epidural injection and confrm correct placement with injec- 4. Epidural Injections tion of radiopaque contrast (Figures 47–24 through Epidural steroid injections (Figure 47–23) are used 47–26). A transforaminal epidural steroid injection for symptomatic relief of pain associated with nerve may be more efective than the standard interlami- root compression (radiculopathy). Clinical improvement appears to be into the foramen of the afected nerve root; contrast correlated with the resolution of nerve root edema. Intrathecal steroid foramen and the injected solution tracks along the injections are not recommended because the ethyl- nerve but not into the epidural space. Unfortunately, migration of the steroid to on the heat produced by current fow from an active the site of injury may not be optimal. The use of a electrode that is incorporated at the tip of a special catheter to direct the injection within the sacral and needle. The epidural injection of contrast needle advanced just to the right of midline for treatment followed by local anesthetic and steroid solution results in of degenerative disc disease and right radicular pain. Depending on the location of the block, the heat- ing temperature generated at the electrode is pre- cisely controlled (60–90°C for 1–3 min) to ablate the nerve without causing excessive collateral tis- sue damage. Tis may be efective for medial branches of the spinal nerves that innervate facet joints. Note extend the spread of the lesion while heating at radiopaque contrast confirmation of the needle in the epidural space. Tese neurolytic agents are not selective, afect- idly drops as gas (carbon dioxide or nitrous oxide) ing visceral, sensory, and motor fbers equally. The probe alcohol (50–100%) causes extraction of membrane tip, which can achieve temperatures of –50°C to phospholipids and precipitation of lipoproteins in –70°C, is introduced via a 12- to 16-gauge catheter. Alcohol causes severe and 50–100 Hz for sensory responses) helps confrm pain on injection, thus local anesthetic is usually correct positioning of the probe. For peripheral nerve blocks, cycles of freezing and thawing are usually admin- alcohol may be given undiluted, but for sympathetic istered. Cryoanalgesia is most commonly used to blocks in which large volumes are injected, it is given achieve long-term blockade of peripheral nerves. Phenol is usually It may be particularly useful for post-thoracotomy painless when injected either as an aqueous solution pain. Patients ofen have neuropathic pain follow- (6–8%) or in glycerol; a 12% phenol solution can be ing thoracotomy or similar surgery. The principal risks of intercostal nerve blocks plasms, especially pancreatic cancer. Chemical Neurolysis intercostal blocks can be helpful for patients with Neurolytic blocks are indicated for patients painful rib metastases. Additional neurodestructive 22 with severe, intractable cancer pain in whom procedures, such as pituitary adenolysis and cor- more conventional therapy proves inadequate or dotomy, may be useful in end-of-life palliative care. The most common at least one diagnostic block with a local anesthetic chemical neurolytic techniques utilized for cancer solution alone should be used initially to confrm the patients are celiac plexus, lumbar sympathetic chain, pain pathway(s) involved and to assess the potential hypogastric plexus, and ganglion impar blocks.
The commercial rewards and increasingly in the field of the pharmacogenetics of ofasuccessfulproductarepotentiallyenormousandprovide safety (i purchase claritin 10mg on line allergy treatment ragweed. Most projects in drug discovery and development cal trial programmes with well-defined patient groups fail generic claritin 10mg fast delivery allergy symptoms 3dp5dt. Indeed the chances of making it through from target (based on phenotypic and genotypic characterisation) purchase claritin 10mg without prescription allergy treatment jobs in quad cities, bet- selection to having a medicine on the market are under 1 ter understanding of the pharmacokinetics and dynamics in 100 purchase claritin 10 mg without prescription allergy forecast sugar land. No benefit produces the wanted effect on protein function and has comes without some risk. More potential drugs and therapeutic targets were • Studies in humans (clinical studies) (see Ch. I then want approach also led to a loss of integration of the to know that it does what I need it to do in terms of the established specialities (chemistry, biochemistry, effect on disease. Theoretically, new drugs could be targeted at selected • Post-licensing (marketing) studies of safety and groups of patients based on their genetic make-up. The (critical) phase of progress from the laboratory to humans is often termed translational science or experimental 3Culliton B J 1994 Nature Medicine 1:1 [editorial]. It was defined as ‘the application of biomedical 30 Discovery and development of drugs Chapter | 3 | research (pre-clinical and clinical), conducted to support eliminate their undesired, properties to create highly selec- drugdevelopment,which aids inthe identificationofthe ap- tive targeted compounds. In principle all molecular struc- propriatepatientfortreatment(patientselection),thecorrect tures capable of binding to a single high-affinity site can dose and schedule to be tested in the clinic (dosing regimen) be modelled. Successful developments these are large robotic screens but newer technologies, in- (1% of compounds that proceed to full test eventually be- cluding use of small molecules using coding tags, allow come licensed medicines) must carry the cost of the failures 5 miniaturisation of the process. It is also obvious that such programmes are likely which is the starting point for medicinal chemistry ‘lead op- to be carried to completion only when the organisations timisation’, depends on the quality of the molecules in the and the individuals within them are motivated overall by compound collection and the nature of the biochemical the challenge to succeed and to serve society, as well as target used for the screen. A previous edition of this chapter included a quote from a paper I wrote from my time in academia and Fragments. If the crystal structure of the protein target is I leave it here: known it is possible to screen small fragments of potential drugs to find those that bind and where they bind. It is then Let us get one thing straight: the drug industry works possible to construct a drug by adding fragments. Unfortunately most drugs fall short 7 successful new medicines of the last few years have been of this ideal. The drug may fail at any used as models for human disease as well as for production stage, including the ultimate, i. It may also fail (due to adverse effects) within the first year after marketing, which constitutes Antisense approaches. Nucleic acid approaches are being a catastrophe (in reputation and finance) for the developer as well as developed to silence gene expression and therefore reduce for some of the patients. Pirated copies of full regulatory dossiers have substantial black market value to competitor companies, who have the expression of culprit proteins. There are various differ- used them to leapfrog the original developer to obtain a licence for ent ways of achieving this including antisense, locked their unresearched copied molecule. Nonetheless, where the treatment aim is 31 Section | 1 | General Sources of compounds Therapeutic targets Chemical libraries Traditional medical uses of natural products Historical compound collections Natural product libraries Combinatorial libraries Empirical understanding of physiology and pathology Rational synthesis Molecular cloning of receptors and signalling molecules Antisense oligonucleotides Genomics Drug discovery screening assays Lead optimisation and candidate selection Drug development Fig. Different types of chemical compounds (top left) are tested against bioassays that are relevant to therapeutic targets, which are derived from several possible sources of information (right). The initial lead compounds discovered by the screening process are optimised by analogue synthesis and tested for appropriate pharmacokinetic properties. The candidate compounds then enter the development process involving regulatory toxicology studies and clinical trials. Understanding of the molecular where a liver effect is desired, it is clear that this ap- basis of immune responses has allowed the definition proach works and provides a potentially attractive ap- of mechanisms by which cellular function is altered by a proach to targeting those proteins or protein–protein legion of local hormones or autacoids in, for example, interactions that are intractable to a small molecule, pep- infections, cancer, autoimmune diseases, organ transplant tide or antibody approach. These processes present targets for therapeutic intervention – hence the rise of immunopharmacology. It is always the case the methods of delivery and the safety and efficiency of that the animal model is never a true model of the vectors used to deliver the genes. So far success has human disease and can only model parts of the been seen in the treatment of certain rare haemopoetic disease process. The trend in industry is to move disorders and genetic immunodeficiency states where fast to the clinic and not to rely too heavily on thegenetransfercanbedoneexvivoandthemodified animal models. Stem cells are impacting drug discovery as they Multinational pharmaceutical companies now scour potentially provide a source of human cells, or even dis- the world for leads from microorganisms (in soil or ease-specific human cells that can be used for screening sewage or even from insects entombed in amber 40 and safety testing. Stem cell therapy is a reality in the form million years ago), fungi, plants and animals. However, the promise is of regenerative luxuriant natural resources) are prominent targets treatments based either on stem cell replacement or chem- in this search and have justly complained of ical stimulation of endogenous stem cells. Many now require 32 Discovery and development of drugs Chapter | 3 | formal profit-sharing agreements to allow such 9 searches. The problem with natural product drug discovery is often that identifying the Pharmacodynamics – to investigate the actions relating to precise active ingredient is hard and the molecules the proposed therapeutic use. This is particularly Pharmacokinetics – the study of the fate of the active true in China where traditional medicines are being substance and its metabolites within the organism (absorp- re-evaluated for effects. The most notable example in tion, distribution, metabolism and excretion of these sub- recent years is the rediscovery of artemisinin for malaria stances). However, such approaches are very unlikely to be commercially • Acute toxicity: single-dose studies that allow qualitative successful in a world that rightly demands true and quantitative assessment of toxic reactions. This includes the • Random screening of synthesised and natural identification of potential target organs and exposure– products. A recent depends on the conditions of clinical use and is defined example is rituximab, a monocloncal antibody that by Regulatory Agencies (Tables 3. Initially developed for the treatment of B Genotoxicity – to reveal the changes that a drug may cause cell lymphoma it was found to be effective for in the genetic material of individuals or cells. Mutagenic suppressing B cell autoimmunity in diseases such substances present a hazard to health because exposure as rheumatoid arthritis. An impure, unstable drug or formulation is use- (pharmacotoxicological) studies must be carried out in conformity with less. In Europe, regulations ensure that all tests on storage in hot, damp climates are vital to therapeutics. Much of the early work in drug discovery is spent try- tests provided that the test results are of comparable quality and usefulness for the purpose of safety evaluation. The pharmacological ing to identify the right molecule with the appropriate and toxicological tests must demonstrate the potential toxicity of the physical and chemical properties to make it reliable as a product and any dangerous or undesirable toxic effects that may occur medicine. The studies must also demonstrate the pharmacological properties of 8Serendipity is the faculty of making fortunate discoveries by general the product, in both qualitative and quantitative relationship to the sagacity or by accident; the word derives from a fairytale about three proposed use in human beings. These studies are also recommended if there is concern about their carcinogenic potential, e.
