X
|
STUDENT DIGITAL NEWSLETTER ALAGAPPA INSTITUTIONS |
|
Advay G. Bhatt, MD
In this regard symptoms stomach ulcer neurontin 300 mg with mastercard, the composition of the extracellular matrix determines the gradients of diffusible cytokines and thereby modulates pivotal biologic processes such as proliferation medicine interaction checker generic 400mg neurontin visa, differentiation medications epilepsy neurontin 300 mg otc, and apoptosis symptoms webmd buy neurontin 400 mg with visa. Two major types of matrices exist: the interstitium, which is synthesized by mesenchymal cells and forms the stroma of organs, and the basement membranes, which are produced by epithelial and endothelial cells. The central feature of all collagen molecules is the stiff structure resulting from lengthy domains of triple-helical conformation. Three polypeptide chains called alpha-chains are wound around one another to generate a rope-like fold. They all share a triple-helical segment of variable length (100 to 450 mm) but differ considerably in the size and nature of their globular domains. It is of interest that 33 genes coding for the different chains are distributed mostly on different chromosomes in the human genome (Table 283-1). Even simultaneously expressed genes, such as those coding for the two alpha1 (I) and one alpha2 (I) chains of the heteropolymeric type I molecule, are located on different chromosomes. The biosynthetic precursor of elastin, tropoelastin, is a linear polypeptide composed of about 700 amino acids and is rich in non-polar amino acids: glycine (>30%), valine, leucine, isoleucine, and alanine. Tropoelastin is synthesized by vascular smooth muscle cells and skin fibroblasts and subsequently incorporated into elastic fibers. Elastic fiber formation involves lysyl oxidase-mediated formation of intermolecular cross-links, called desmosine and isodesmosine. Fibronectins are dimeric cell adhesion glycoproteins composed of two disulfide-bonded subunits and found in rather large quantities in blood plasma (0. Because fibronectin plays a major role in morphogenesis and tissue remodeling, regulation of fibronectin biosynthesis by growth factors and cytokines has been studied. The thrombospondins consist of three or five disulfide-bonded subunits that, comparable to fibronectin, contain a number of distinct domains with specific binding sites for macromolecules occurring at cell surfaces or in extracellular matrices. A number of structural glycoproteins have been isolated from various types of cartilage. A 148-kd cartilage matrix protein leucin-rich repeat is prominent in tracheal cartilage and growth cartilage but not present in normal articular cartilage. Hyaluronic acid, also called hyaluronan is an exception among the glycosaminoglycans because this polymer of glucuronic acid and glucosamine is not sulfated and not attached covalently to a protein core connected via a link protein. With respect to their function, they have been referred to as a "multipurpose glue. This molecule binds to collagen and fibronectin through its heparan sulfate chains and mediates cell adhesion. The fibronectin molecule contains a series of functional domains that bind the indicated ligands. The typical features of the laminin molecule are a thread-like long arm terminating in a globular domain and three short arms, each consisting of two globular domains separated by short linear segments. The different laminins (1 to 11) serve in very specialized basement membranes such as the dermoepidermal and myotendinous junctions. They control permeability of the glomerular basement membranes and have also been implicated in the anchorage of acetylcholinesterase to the neuromuscular junction. Because integrins localize in known junctional regions where actin bundles and myofibrils terminate at the cell surface, the major function of integrin receptors appears to be the linkage of extracellular matrix molecules with the intracellular cytoskeletal network. That extracellular matrix components may influence gene expression by signal transduction is shown by the finding that fibronectin degradation products induce, via the fibronectin receptor, collagenase and stromelysin gene expression. The pivotal role of these receptors related to infectious diseases is further illustrated by the observation that bacteria use specific receptors to adhere to host connective tissue. For example, it has been shown that certain strains of Escherichia coli express a fibronectin receptor that is involved in colonization. Joint injury and cartilage degradation result when synovial cells with activated proto-oncogenes form an invasive lesion called pannus. Arthus, in 1903, then provoked "local anaphylaxis" in rabbits by repeated injections of antigen intradermally; inflammation and necrosis resulted. Opie, in 1924, confirmed that the lesions of Arthus were local antigen-antibody reactions in which inflammation was mediated by white cells and that proteolysis was crucial. Indeed, it was found that the Arthus lesions could also be provoked by planting antigen in the skin, followed by specific antibody intravenously (the "passive Arthus reaction"), or by injecting antibody in the skin, followed by antigen intravenously (the "reversed passive Arthus reaction"). In each case, one was dealing with the interactions at a surface of neutrophils that had been attracted by immune complexes localized beneath the endothelium of blood vessels. These products-especially superoxide (O2 ·-), peroxide (H2 O2), and proteases-cause irreversible tissue injury. Predictably, Arthus reactions can be abolished by rendering animals deficient in complement or in neutrophils. Antiproteases or antihistamines are somewhat less effective inhibitors of the Arthus lesion; antiplatelet agents or anticoagulants are useless. It is generally agreed that the local Arthus lesion is one model of immune complex vasculitis in humans that is also due to the interactions of neutrophils with immune complexes and complement. The cells take up self-associating complexes of IgG-IgG rheumatoid factor, as well as the more common IgM/IgG complexes; complement is predictably activated. In the Shwartzman model (bottom), intradermal injection of the antigen leads to intravascular alternative pathway complement activation. The two lesions require a latent, or "preparatory," period of 6 to 24 hours, and the 2nd injection need not be of the same filtrate (see. Locally or systemically, the "preparatory" injection of endotoxin promotes modest adhesion of neutrophils to post-capillary venules, with escape of some of the white cells from the vessels. The Shwartzman phenomenon can be elicited by 2nd injections of not only endotoxin but also various polyanions, glycogen, or antigen/antibody complexes, all of which share with endotoxin the capacity to activate complement via the alternative pathway. Moreover, local and systemic Shwartzman reactions can be prevented by rendering animals deficient in complement or neutrophils. The 2nd, or provocative, injection of endotoxin, glycogen, or immune complexes now causes massive neutrophil clumping (homotypic adhesion). Each chemoattractant engages a G-protein-linked receptor, and each stimulates intracellular proton and calcium fluxes; subplasmalemmal actin assembly; activation of phospholipases A2, C, and D and phosphatidylinositol 3-kinase; formation of inositol 1,4,5-triphosphate, phosphatidylinositol 4,5-biphosphate, and phosphatidylinositol 4,5-triphosphate; release of arachidonate; and de novo synthesis of phosphatidate and diacylglycerol, followed by activation of protein kinase C. During their maturation in the bone marrow, neutrophils acquire their characteristic populations of intracellular granules. The vacuole then fuses with lysosomal granules to form a chamber called the "phagolysosome," and the granule contents are released into this chamber in a process called "covert degranulation. This "overt degranulation," a mechanism for extracellular secretion, has been termed "regurgitation during feeding," or when the material is too large to be ingested. Because hypochlorous acid is formed in the neutrophil after the interaction of myeloperoxidase, chloride anion, and H2 O2 derived from O2 ·- via the reduced Figure 284-3 Release of mediators of inflammation by the human neutrophil. When neutrophils are engaged by chemoattractants of bacterial origin (formyl-methionylleucyl-phenylalanine, a bacterial peptide analogue), by chemoattractants from the complement sequence (C5a), or by immune complexes, they release lysosomal enzymes from intracellular granules to the outside (overt degranulation), assemble and activate the reduced nicotinamide-adenine dinucleotide phosphate oxidase that forms toxic oxygen species (O2 ·-, H2 O2 etc. In addition to contributing to the formation of hypochlorous acid, oxygen metabolites can also damage connective tissue directly. Neutrophils respond to the engagement of receptors for chemoattractants or immune complexes by mobilizing arachidonate from the sn-2 position of phospholipids. Data on the remodeling of lipids show that not only phospholipase A2 activity but also the activity of phospholipase C and D can explain these changes (see below). However, arachidonic acid does not engage its own specific G-protein-linked cell surface receptor. Acting in an autacoid fashion, it is a major agonist in arachidonate-mediated inflammation. Signaling via Fcgamma receptors and receptors for chemoattractants differs with respect to some details, but the general process of stimulus-response coupling is similar, and neutrophils do not differ in these general pathways from other cells of inflammation. In contrast, both diacylglycerol and phosphatidic acid continue to increase over the course of the next 120 to 300 seconds. For neutrophils or macrophages to respond over time and in space, two signals must be generated: a short "triggering" signal with an immediate increase in intracellular messengers. Influx of extracellular Ca begins approximately 5 seconds after Ca has been released from intracellular sites and while inositol triphosphate levels are still dropping. At least 16 alpha- as well as multiple beta- and gamma-subunits have been identified. Immunoblot analysis with subunit-specific 1485 antisera have identified Galphai2,3, Galpha8, Gbeta1,2, and Ggamma2 in human neutrophil membranes. Galphai2 is most intimately involved in neutrophil activation by chemoattractants. Both ras-related proteins and the gamma-subunit of G proteins are targeted to membranes by a series of post-translational modifications of their carboxyl termini that involves prenylation (addition of a 15- or 20-carbon polyisoprene lipid), proteolysis, and carboxyl methylation. Carboxyl methylation, the only reversible step in this processing, is associated with neutrophil activation and plays a key regulatory role in signal transduction.
Because these films are a part of most routine medical examinations treatment quinsy generic 100mg neurontin with mastercard, they are a useful tool for detecting disease symptoms west nile virus purchase 100mg neurontin overnight delivery, as well as evaluating the severity of known disease treatment neutropenia generic neurontin 100 mg visa, documenting the progress of the disease treatment renal cell carcinoma buy neurontin 800 mg lowest price, and assessing the efficacy of treatment. The break in the contour of this border of the heart indicates the caval-atrial junction. Some patients are able to lower their diaphragms sufficiently during inspiration to uncover a small, straight segment of the inferior vena cava between the diaphragm and the right atrium. The uppermost bulge represents the aortic knob, the most distal portion of the aortic arch where it turns downward to become the descending aorta. The prominence below the knob is formed by the main pulmonary artery and the subvalvular portion of the outflow tract of the right ventricle. The lowermost third of this border represents the anterolateral wall of the left ventricle. The heart lies in the anterior portion of the chest, and the right ventricle abuts the lower third of the sternum. Air-containing lung interposed between this portion of the heart and the anterior chest wall forms the "retrosternal clear space. Its upper half is formed by the back of the left atrium, whereas the lower half represents the posterior wall of the left ventricle. The shadow of the inferior vena cava is usually seen in the lateral projection to extend obliquely upward and anteriorly from the diaphragm to enter the posterior aspect of the right atrium. The lowermost posterior contour of the left ventricle curves anteriorly and 178 Figure 41-1 Normal radiographic anatomy, magnetic resonance images. Alterations in the contour of the heart usually reflect dilation and/or hypertrophy of the chambers. Many times the pattern of these changes, together with the appearance of the pulmonary vasculature, points to a specific underlying cardiac abnormality. Cardiac hypertrophy is more difficult to recognize inasmuch as the thickened myocardium tends to encroach on the ventricular lumen more than extending outward and enlarging the cardiac silhouette. Similarly, patients with restrictive cardiomyopathy may be in severe congestive failure with a normal-appearing heart. On the other hand, an enlarged heart always indicates the presence of cardiac or pericardial disease. The cardiothoracic ratio is measured by dropping a vertical line through the heart and measuring the greatest distance to the right and left cardiac borders. The transverse thoracic diameter is the greatest width of the chest, measured from the inner surfaces of the ribs. Severe aortic stenosis with a 95-mm systolic gradient across the valve is present. The heart, although considerably hypertrophied, is normal in size and configuration. The greatest distances to the right cardiac border (A) and to the left cardiac border (B) are then measured. With expiration, as the diaphragm moves up, the vertical diameter of the heart is shortened and its transverse diameter increases. Because heart size is estimated primarily from its width, the heart appears larger on expiratory films. On a properly positioned frontal chest film, a reasonable degree of inspiration is indicated if the diaphragm is lowered to at least the level of the posterior portion of the 9th rib. When the anteroposterior diameter of the chest is small, the heart may be compressed between the sternum and the spine so that it splays to one or both sides. For this reason, the heart often appears enlarged in patients with the straight back syndrome or with a pectus excavatum deformity of the sternum. This point is important because chest films are exposed at random with reference to the cardiac cycle, and the apparent size of the heart may be different on two films of the same patient made at different times. In the majority of cases, the difference in the transverse cardiac diameter between systole and diastole is small, no more than several millimeters. This increase in thickness occurs in mitral disease when the left atrium enlarges and protrudes posteriorly Figure 41-3 Left atrial enlargement in mitral valve disease. A, Patient 1: the enlarged left atrium causes the central portion of the cardiac silhouette to be abnormally dense. The right border of the atrium is seen within the right side of the cardiac silhouette. The region of the left atrial appendage (white arrow) is slightly concave because this structure was resected at a previous mitral commissurotomy. The right border of the left atrium is then silhouetted where it abuts the right lung and its contour is seen within the cardiac silhouette. Conversely, when the right atrium also enlarges, as is common in long-standing Figure 41-5 Left ventricular aneurysm. Furthermore, the radiologic technique used for chest films is chosen to provide optimal images of the lungs. For the same reason, the position of the left main bronchus often cannot be clearly visualized through the mediastinal shadow. A more sensitive sign of left atrial enlargement in the frontal projection is dilation of the left atrial appendage. It forms the part of the left heart border between the pulmonary artery segment and the left ventricular segment. The shape of the dilated left ventricle depends to a large extent on the underlying cause. When it is due to insufficiency of the aortic or mitral valve, the ventricle elongates and its apex is displaced downward, to the left, and posteriorly. In the lateral view, the downward extension of the enlarged left ventricle covers more of the vena caval shadow than normal, and the crossing point of their posterior borders occurs nearer to the diaphragm than normal. Enlargement of the left ventricle produces a smoothly curved dilatation of the lower portion of the cardiac silhouette. The main pulmonary artery (arrow) and the right pulmonary artery are markedly dilated. The left pulmonary artery was also dilated but is hidden by the heart in this view. Accentuation of the curvature of the lower right cardiac border and enlargement of the cardiac silhouette to the right are caused by dilatation of the right atrium. Furthermore, on a routinely exposed film, calcific deposits are not easily seen because of the overlapping shadows of the descending aorta (arrows) and the spine. Enlargement of only the right chambers of the heart is seen in severe pulmonary hypertension without coexisting left heart failure, in bacterial endocarditis of the tricuspid and/or pulmonic valve, and in the carcinoid syndrome. Dilatation of the right atrium causes an accentuation and outward bowing of the curvature on the lower half of the right cardiac contour in the frontal view. Even moderate right ventricular enlargement may produce no abnormality in this view other than some elevation of the main pulmonary artery. It is not often possible to distinguish between biventricular enlargement or dilatation of one or the other of the ventricles. As the right ventricle enlarges, its area of contact with the sternum increases and tends to obliterate the retrosternal clear space in the lateral view. Valvular calcification most often involves the mitral and aortic valves and usually indicates significant stenosis. Because the two valves are in contact-inserting on a common fibrous tendon-determining which valve is calcified may be difficult. The curvilinear calcific deposit is within the scarred lower portion of the ventricular septum. Calcification of the myocardium in coronary artery disease indicates a previous transmural infarct and frequently a ventricular aneurysm. The calcified scar is visualized as a fine, curvilinear density, most commonly on the anterolateral aspect of the heart, where it is seen best in the frontal view. Often, pericardial calcium is distributed primarily over the interventricular sulcus and the atrioventricular grooves, but when extensive, the deposits may coalesce and completely surround the heart. Although the calcium is often not deposited in the areas of high-grade stenosis, a very strong correlation exists between the extent of coronary artery calcification and the extent of coronary arterial sclerosis. Calcification of the coronary arteries is difficult to visualize on chest films because the deposits are thin and their shadows are blurred by the motion of the heart. Fluoroscopy is more sensitive but not as accurate as fast computed tomographic scanning for detecting or quantifying coronary artery calcification. A large, thick, calcific plaque (arrow) lies just below the level of the left upper lobe bronchus.
Intravenous beta-blockers and calcium channel blockers can also be used for the same purpose treatment vitiligo cheap 800 mg neurontin with mastercard. The usual sinus rate varies between 60 and 100 beats per minute medicine 1975 cheap 300mg neurontin visa, determined by physiologic need and modulated through the autonomic nervous system symptoms 9dpo bfp cheap neurontin 600 mg. In healthy persons medications similar to gabapentin order neurontin 600 mg online, however, rates of 50 beats per minute are not unusual, and rates as low as 30 beats per minute may be recorded during sleep. The sinus node may fire, but the impulse to the atrium can be delayed or periodically interrupted with loss of P wave (see. Because of the proximity of aortic and mitral valves to the distal His bundle and proximal bundle branches, annular calcification or valve surgery can cause acute or chronic intra-His and infra-His block. Patients with congenital heart block may not appreciate their potential for more active lifestyle because of the lack of a reference point but feel much better when an appropriate heart rate acceleration can be achieved after pacemaker therapy. Vasovagal (neurocardiogenic) syndromes are a rather common cause of syncope in relatively healthy populations (see Chapter 50); in the vast majority of these cases, vasodepression (hypotension) is the primary cause of syncope, and rate control alone does not relieve symptoms. Myerburg R, Kessler K, Castellanos A: Recognition, clinical assessment and management of arrhythmias and conduction disturbances. Ventricular ectopy is exceedingly rare in infants but increases in frequency with age. Likewise, among patients with valvular heart disease, sudden death is rare when ventricular function is normal. Classically, a surrounding region of depressed conductivity protects the focus by creating complete entrance block that prevents supraventricular beats from resetting the focus. Although helpful in most situations, these morphologic criteria are not 100% specific. Intravenous lidocaine is often chosen as a first-line agent because it can be administered rapidly (bolus dose of 1-1. Coronary revascularization or antianginal medical therapy may be sufficient to control arrhythmias due to acute ischemia. Antiarrhythmic medications, such as lidocaine, are also useful to control recurrent arrhythmias in this setting. The strongest risk factors for sustained ventricular arrhythmias late after myocardial infarction are depressed left ventricular function and increased frequency and complexity of ventricular ectopy. Catheter ablation may have an adjunctive role for controlling frequent ventricular arrhythmias. The signal-averaged electrocardiogram and invasive programmed stimulation (see Chapter 50) have limited sensitivity and specificity for predicting future risk. Patients develop re-entry involving diseased portions of the right ventricle but rarely develop right ventricular failure. Magnetic resonance imaging and electron-beam computed tomography (see Chapters 44 and 45) can demonstrate fatty replacement of the right ventricle, thinning of the right ventricular wall, and wall motion abnormalities. Therapeutic modalities for treating arrhythmogenic right ventricular dysplasia include antiarrhythmic medication and implantation of a cardioverter-defibrillator. Catheter ablation, while rarely curative, may ameliorate frequent ventricular arrhythmias. Right ventricular outflow tract tachycardia can be cured by catheter ablation (see Chapter 53). Failure of these channels to activate normally prolongs the action potential duration and provokes early afterdepolarizations. A liquid protein diet, starvation, central nervous system disease, and bradyarrhythmias may also predispose to TdP. Therapy for severe digitalis-toxic arrhythmias includes infusion of digoxin immune Fab fragments, which may be life saving. Prodromal symptoms in the 2 weeks preceding collapse may include fatigue, dyspnea, and chest pain. Most survivors of cardiac arrest have structural heart disease, especially coronary artery disease. Other causes include repair of congenital anomalies such as transposition of the great arteries and tetralogy of Fallot (see Chapter 57). Left ventricular function can be assessed by contrast ventriculography, radionuclide ventriculography, or echocardiography. Chronic ischemic heart disease with transient supply/demand imbalance-thrombosis, spasm, physical stress 2. Pacemaker batteries, which are lithium iodide cells that typically have a life span of 7 to 8 years, now often weigh less than 30 g. Atrial leads usually are positioned in the right atrial appendage, and ventricular leads are placed in the right ventricular apex. Newer electrode designs, such as porous carbon or steroid-eluting electrodes, have resulted in lower acute and chronic pacing thresholds. The mode of pacing is described in shorthand fashion by a three- to five-letter code. In general, pacemakers are implanted either to alleviate symptoms caused by bradycardia or to prevent severe symptoms in patients who are likely to develop symptomatic bradycardia. Third-degree atrioventricular block with pauses 3 seconds or with an escape rate <40 beats per minute in awake patients C. Carotid Sinus Syndrome: Recurrent Syncope or Near-Syncope due to Carotid Sinus Syndrome Please see the Cheitlin et al reference on page 252 (J Am Coll Cardiol 31:1175-1209, 1998). After a symptomatic bradycardia has been documented, a correctable cause for the bradycardia should be excluded before a pacemaker is implanted. Correctable causes for symptomatic bradycardias include hypothyroidism, an overdose with drugs such as digitalis, electrolyte disturbances, and several categories of medications, most commonly beta-adrenergic blocking agents (administered either orally or in the form of eyedrops for glaucoma), calcium channel blocking agents, and antiarrhythmic medications (see Chapter 51). At times, a pacemaker is necessary to allow continued treatment with a medication that is responsible for the bradycardia, such as in a patient who develops symptomatic sinus bradycardia after initiation of therapy with a beta-adrenergic blocking agent for paroxysmal atrial fibrillation associated with a rapid ventricular response. Complications related to the implantation procedure occur in less than 2% of patients and include pneumothorax, perforation of the atrium or ventricle, lead dislodgement, infection, and erosion of the pacemaker pocket. Thrombosis of the subclavian vein occurs in 10 to 20% of patients and is more likely in the presence of multiple leads; it rarely causes symptoms. Please see the Cheitlin et al reference on page 252 (J Am Coll Cardiol 31:1175-1209, 1998). During long-term follow-up after pacemaker implantation, potential problems include failure to pace, failure to capture, and changes in pacing rate. These problems may be a manifestation of suboptimal programming, a lead fracture or insulation break, generator malfunction, or battery depletion. Temporary pacing is used to stabilize patients awaiting permanent pacemaker implantation, to correct a transient symptomatic bradycardia due to drug toxicity or a metabolic defect, or to suppress torsades de pointes by maintaining a rate of 85 to 100 beats per minute until the causative factor has been eliminated. The most common complication of temporary pacemakers is infection; this risk is minimized by limiting the use of a pacemaker lead to 48 hours. In emergent situations, ventricular pacing can be instituted immediately by transcutaneous pacing using electrode pads applied to the chest wall. Direct-current defibrillators store an electrical charge and discharge it across two paddle electrodes in a damped, sinusoidal waveform. The shock terminates arrhythmias caused by re-entry by simultaneously depolarizing large portions of the atria or ventricles, thereby causing re-entry circuits to extinguish (see Chapters 51 and 52). Whenever cardioversion or defibrillation is performed on an elective basis, the patient should be in a fasting state. Intravenous access to a peripheral vein should be established, and oxygen, suction, and equipment needed for airway management should be readily available. Transthoracic shocks are painful, and drugs commonly used for anesthesia or amnesia include short-acting barbiturates such as methohexital or a short-acting amnestic agent such as midazolam. These two electrode configurations result in similar success rates of cardioversion and defibrillation. An important variable affecting the success of cardioversion/defibrillation is the shock strength. Because cardioversion of atrial fibrillation (see Chapter 51) may be complicated by thromboembolism, anticoagulation with warfarin is generally necessary for 3 weeks before cardioversion and for 1 month after cardioversion whenever atrial fibrillation has been present for 48 hours or more. The 3-week period of anticoagulation before cardioversion can be eliminated if no atrial thrombi are seen on a transesophageal echocardiogram, but anticoagulation for 1 month after cardioversion still is necessary to prevent thrombus formation due to transient, post-conversion atrial stunning. An initial energy level of 50 J is appropriate for cardioversion of atrial flutter. If atrial fibrillation must be treated on an urgent basis, for example, in a patient with the Wolff-Parkinson-White syndrome who has a very rapid ventricular rate and hemodynamic compromise, an initial shock of 200 J should be followed by 360-J shocks, as needed.
Endocrine agents are therefore often given for many years treatment ringworm buy neurontin 800 mg free shipping, whereas cytotoxic agents are usually given over a time course measured in months treatment uterine cancer order neurontin 600 mg on-line. An important concept in cancer chemotherapy is that cellular killing with cytotoxic agents follows first-order kinetics treatment gout buy discount neurontin 800mg on line, with a given dose of drug killing only a fraction of the tumor cells medicine in motion buy 600 mg neurontin. This concept was based on the hypothesis that giving drugs with differing mechanisms of action may achieve synergistic antitumor effects while simultaneously retarding the rate of development of drug resistance. For example, cisplatin has demonstrated clear-cut synergy with etoposide in testicular cancer and small cell lung cancer and with fluorouracil in both head and neck and esophageal cancer. New drugs entering clinical trials are normally first tested in patients with a large tumor burden of metastatic cancer who have relapsed from known effective chemotherapy regimens. The presence of the blood-brain barrier has been a major obstacle to the development of chemotherapy for primary or metastatic tumors in the brain. For many of the drug-responsive tumor types (see Table 198-2), major cytoreduction occurs with initial chemotherapy. Some months to years thereafter, however, tumor regrowth occurs and continues even though the same drugs are reinstituted. This observation usually reflects the acquisition of drug resistance by the tumor to the specific drugs. Most drug resistance is considered to result from the high spontaneous mutation rate of cancer cells, which leads to the development of heterogeneous subpopulations, some of which exhibit resistance to various drugs. Drugs pumped out of the cancer cell by the P-glycoprotein include natural products such as plant alkaloids (vincas, podophyllotoxins, taxol), antibiotics (dactinomycin, doxorubicin, daunorubicin), and some synthetic agents. The P-glycoprotein is normally expressed in tissues such as the gut and the kidney, perhaps to deal with toxic products in the environment. A series of non-cytotoxic drugs has been identified to reverse drug resistance mediated by P-glycoprotein. Although verapamil is not an ideal chemosensitizer (because of its cardiovascular side effects), other potential chemosensitizers are now being tested in an effort to identify more effective and less toxic chemosensitizers. This transmembrane protein is believed to function as an energy-dependent efflux pump or drug transporter. It has acceptor sites to which various natural product anticancer drugs bind, after which they are pumped out of the cell. Taken with other prognostic characteristics, such flow cytometry assays may aid in identifying patients who should receive adjuvant chemotherapy. This approach is currently being applied to patients with stage I breast cancer in an effort to decide which patients are at higher risk for recurrence. Additionally, in the absence of adjuvant therapy, tumors that are estrogen or progesterone receptor positive take longer to recur and have a better overall prognosis than tumors that are receptor negative. An antibody to this receptor can cause tumor regression in patients whose breast cancers overexpress this protein. Abnormalities in expression of p53, the tumor suppressor gene, have been associated with a worse prognosis when present in a wide variety of solid tumors. Chemosensitivity assays appear to predict drug resistance but are somewhat less accurate for predicting which drugs will be useful for an individual patient. For example, fresh sarcoma cells in short-term mixture have been shown to be useful for evaluating potential anticancer effects of various folate analogues as measured by inhibitors of thymidylate synthesis in a whole-cell assay. Although intrinsic drug sensitivity appears to be the most critical determinant of response to chemotherapy, pharmacokinetic factors related to the route of administration, bioavailability, metabolism, and elimination are probably of greater importance in cancer therapy. Many cytotoxic agents have a steep dose-response curve and a resulting narrow therapeutic index. Because of the steep dose-response relationship, doses of most cytotoxic agents are calculated in relation to body surface area, a more accurate approach than dose calculations based on body weight. For patients presenting with hypercalcemia or other complications of myeloma, oral melphalan therefore seems undesirable, because such patients need to achieve effective plasma levels immediately. The intravenous route of drug administration is preferable for most cytotoxic anticancer drugs, because it ensures adequate plasma levels while minimizing compliance problems. With the advent of vascular access devices such as subcutaneous ports, external catheters, and infusion pumps, outpatient continuous infusion chemotherapy can now be used for stable drugs such as fluorinated pyrimidines, anthracyclines, and Vinca alkaloids. Subcutaneous administration can be used effectively with drugs such as cytarabine, interferon-alpha, and erythropoietin. Subcutaneous dosing provides more sustained plasma levels than can be obtained with intravenous administration. For metastatic colon cancer limited to the liver, hepatic artery catheterization for arterial infusion of 5-fluorodeoxyuridine or 5-fluorouracil can be used effectively by connection of the catheter to an external pump or to an implantable perfusion pump. In either instance, arterial infusions are often administered for 14 days, followed by a similar rest period. A relatively high objective response rate of metastatic colon cancer in the liver can be obtained by this means, but this route is ineffective for metastases outside the liver. Regional infusion or isolated perfusion has been used with melanomas and sarcomas of the lower extremity. With melanoma metastases of the lower extremity, melphalan or cisplatin has been administered in this fashion with or without regional hyperthermia. In ovarian cancer, intraperitoneal chemotherapy is being studied as a follow-up to cytoreductive surgery. Preferred drugs for intraperitoneal administration are those that tend to be limited largely to the peritoneal cavity, have good properties for tumor penetration, and produce little or no local toxicity. Mitoxantrone, fluorodeoxyuridine, and cisplatin have these favorable characteristics and can be quite useful. With each of these drugs, the intraperitoneal concentration can be 1000-fold higher than measured in the systemic circulation. Other agents sometimes used in intraperitoneal administration include thiotepa, fluorouracil, and methotrexate. Intrathecal methotrexate has been used effectively for acute lymphoblastic leukemia as an adjuvant to initial systemic chemotherapy and has reduced the frequency of central nervous system relapse in patients in complete peripheral remission. Objective measurement of tumor shrinkage with medical or radiation therapy has prognostic importance. Cure or significant prolongation of survival occurs in patients who achieve complete response (disappearance of all evidence of cancer). Patients achieving partial responses generally have palliation of symptoms and usually have a prolonged period without tumor growth. Tumor markers in the blood or urine can be useful in monitoring response to therapy (see Chapter 192). Response to adjuvant chemotherapy cannot be evaluated by these methods, because insufficient tumor usually remains to employ physical or imaging studies or tumor markers. However, in the neoadjuvant setting in which chemotherapy is used before local surgery, the response to chemotherapy provides an "in vivo sensitivity test" to determine whether the employed agents can provide effective therapy after surgery. Therefore, it is wise to use effective and well-established combination protocols with known side-effect profiles rather than to improvise combinations. The development of new combinations of standard drugs is best done in the research setting. All alkylating agents can potentially induce ovarian or testicular failure as well as acute leukemia. Cyclophosphamide (Cytoxan) is the most widely used alkylating agent and is effective in the treatment of both hematologic malignancies and solid tumors. It does not have significant vesicant effects, because it is a prodrug that requires bioactivation in the liver. A commonly used single-agent dosage schedule for intravenous cyclophosphamide is 1. Cyclophosphamide produces a less severe pattern of myelosuppressive toxicity than other alkylating agents; it can cause severe neutropenia but usually of relatively short duration, and thrombocytopenia is less severe than with other alkylators. Both cyclophosphamide and a related analogue, ifosfamide (Ifex), can cause hemorrhagic cystitis. Bladder toxicity can be blocked by administration of the uroprotective agent mesna (Mesnex), which is concentrated in the urine and inactivates the toxic metabolite acrolein. Ifosfamide causes somewhat less hematologic toxicity than other alkylating agents and at present is used mostly for second-line therapy. Melphalan (Alkeran) is L-phenylalanine mustard and gains access to cells through an amino acid transport system. Melphalan is commonly given orally in a dosage of 10 mg/m2 /day for 4 days every 3 to 4 weeks. Melphalan is commonly used in the treatment of multiple myeloma and ovarian cancer and occasionally for other tumor types.
Purchase neurontin 100 mg mastercard. SHINee - Symptoms [3D Audio].
