It includes such factors immunity order zocor visa cholesterol score of 8, may have a signifcant role in resistance of a group as protection by the skin buy cheap zocor 40mg on-line cholesterol lowering foods grapefruit, mucous membranes discount zocor 10 mg with visa cholesterol test fasting vs. nonfasting, lysozyme in (herd) of humans or other animals against an infectious dis- tears, stomach acid, and numerous other factors. Elimination of reservoirs of the disease agent natural killer cells, complement, and cytokines represent key may be as important as specifc immunity in diminishing participants in natural innate immunity. The successful vaccination infected under normal circumstances by selected microor- of most members of a population against a selected pathogen ganisms that usually infect animals. This may be altered in may protect non-immune individuals in the group, whose the case of profound immunosuppression of humans, as in vulnerability is diminished because the pathogen cannot the case of acquired immune defciency syndrome in which become established in the vaccinated population. Molecules, Cells, and Tissues of the Immune Response 153 Lactoferrin is a protein that combines with iron and com- Protective immunity refers to both natural, nonspecifc petes with microorganisms for it. This represents a nonanti- immune mechanisms and actively acquired specifc immu- body humoral substance that contributes to the body’s natural nity that result in the defense of a host against a particular defenses against infection. By combining with induced either by active immunization with a vaccine pre- iron molecules, it deprives bacterial cells of this needed pared from antigens of a pathogenic microorganism or by substance. Lactoperoxidase is an enzyme present in milk and saliva that may be inhibitory to a number of microorganisms and Protective antigens are the antigenic determinants of a serves as a nonantibody humoral substance that contributes pathogenic microorganism that stimulate an immune response to nonspecifc immunity. Its mechanism of action resembles that can protect a host against an infection by that microor- that of myeloperoxidase. Thus, these particular antigenic specifcities can be used for prophylactic immunization in vaccines to immunize Nonsterile immunity: See premunition. Acquired immunity is protective resistance against an Protective epitopes are antigenic determinants of a patho- infectious agent generated as a consequence of infection with genic microorganism that stimulate a protective immune a specifc microorganism or as a result of deliberate immu- response against that same microorganism. Preemptive immunity refers to resistance shown by virus- Cellular immunology is the study of cells involved in infected cells to superinfection with a different virus. Artifcial passive immunity refers to the transfer of immu- Active immunity is protection attained as a consequence of noglobulins from an immune individual to a nonimmune, clinical or subclinical infection or deliberate immunization susceptible recipient. It is a type of adaptive immunity in which lymphocytes are activated in response to Passive immunity is a form of acquired immunity induced a foreign antigen to which they have been exposed. Compare by the transfer of immune serum containing specifc anti- with passive immunity. Examples of passive immunity Artifcially acquired immunity is the use of deliberate are the transfer of IgG antibodies across the placenta from active or passive immunization or vaccination to elicit pro- mother to fetus or the ingestion of colostrum-containing anti- tective immunity as opposed to immunity which results from bodies by an infant. Antitoxins generated to protect against unplanned and coincidental exposure to antigenic materials, diphtheria or tetanus toxins represent a second example of including microorganisms in the environment. The trans- fer of specifcally sensitized lymphoid cells from an immune Specifc immunity refers to an immune state in which anti- to a previously nonimmune recipient is termed adoptive body or specifcally sensitized or primed lymphocytes recog- immunization. By contrast, immunologically serum can be used for the temporary protection of individu- competent cells may interact with antigen to produce specifc als exposed to certain infectious disease agents. Humoral immune response is a host defense mediated by antibody molecules found in the plasma, lymph, and tissue Gravity and immunity: Space fight has been associated fuids. This type of immunity protects against extracellular with the development of neutrophilia, slight T cell lym- bacteria in foreign micromolecules. Humoral immunity may phopenia, and diminished blastogenic responsiveness of be transferred passively with antibodies or serum containing T cells in postfight blood samples. Changes have also Humoral antibody is found in the blood plasma, lymph, been observed in postfight concentrations of immuno- and other body fuids. Humoral antibody, together with com- globulins, complement components, lysozyme, interferon, plement, mediates humoral immunity which is based upon and α2-macroglobulin. IgA and IgM rose but IgG remained constant dur- immunodefciency worldwide is malnutrition. No defects in humoral immunity have malnutrition has an adverse effect on immunity, increases been noted. Serum antibody responses are usually unaffected in Exercise-induced immunosuppression or immunoenhance- protein-energy malnutrition. But cytes is intact and metabolic destruction of microorganisms these increases return to preexercise levels within a few is decreased as is synthesis of various cytokines including hours following its cessation. Acute exercise is followed cell-mediated immunity and diminished antibody responses. It leads to impaired lympho- have been demonstrated following long distance running. IgG, IgM, and IgA levels as well as the ability to synthesize antibody to tetanus toxoid antigen are not compromised by Vitamin A and immunity: A defciency of vitamin A com- exercise. Exercise prior to exposure to infection diminishes promises acquired, adaptive, antigen-specifc immunity. The morbidity or mortality, yet exercise during an infection pro- defciency has been linked to atrophy of thymus, spleen, duces the reverse effect. Prolonged intense exercise is fol- lymph nodes, and Peyer’s patches pointing to major alterations lowed by some immunosuppression. Vitamin A defciency altered by physical exercise are related to the neuroendocrine is also associated with impaired ability to form an antibody changes such as those that occur in response to physical or response to T cell-dependent antigens such as tetanus toxoid, psychological stress. It is also linked to decreased antibody responsiveness to T cell-independent antigens such Nonspecifc immunity: Refers to mechanisms such as as pneumococcal polysaccharide and meningococcal poly- phagocytosis that nonspecifcally remove invading micro- saccharide. Vitamin A defciency also compromises natural organisms, as well as the action of chemical and physical innate immunity since it is necessary for maintenance of barriers to infection such as acid in the stomach and the mucosal surfaces, the frst line of defense against infection. Other nonspecifc protective factors include lysozyme, Immune effector cells that mediate nonspecifc immunity β lysin, and interferon. Nonspecifc or natural immunity include polymorphonuclear cells, macrophages, and natural does not depend on immunologic memory. Neutrophil phagocytosis is diminished by cells represent an important part of the natural immune Vitamin A defciency, and viral infections are more severe cell system. Molecules, Cells, and Tissues of the Immune Response 155 Immunologically, vitamin A may serve as an adjuvant to ele- Vitamin E and immunity: Vitamin E is required by the vate antibody responses to soluble protein antigens in mice. It is a major antioxidant that protects cell the adjuvant effect is produced whether vitamin A is given membranes from free radical attack. Vitamin and stimulates cytotoxic cells, natural killer cells, phago- B defciency induces marked changes in immune function, cytosis by macrophages, and mitogen responsiveness. Thymic hormone activity is dimin- immunostimulatory action of vitamin E renders it useful for ished and lymphopenia occurs. Vitamin B defciency sup- therapeutic enhancement of the immune response in patients. Folate and vita- lation of immunity is particularly important in the elderly in min B12 defciencies are linked to diminished host resistance whom infectious disease and tumor incidence increase with and impaired lymphocyte function. Vitamin E facilitates host defense by inhibiting increases ciency suppresses humoral antibody responses to antigens. In vitro, vitamin E has been shown to stimulate ate interfering action on immune function. Intake of micronutrients, including the B complex which may be a mechanism to enhance immune responses vitamins two to three times higher than the U.
The extrinsic variety encompasses opsonin nosuppressive agents discount zocor 10mg otc cholesterol recommendations, corticosteroid-induced interference defciencies secondary to antibody or complement factor def- with phagocytic function order zocor online pills ideal cholesterol ratio for an individual would include, neutropenia order 40mg zocor with visa what is cholesterol in shrimp, or abnormal neutro- ciencies, suppression of phagocytic cell numbers by immuno- phil chemotaxis. Intrinsic phagocytic dysfunction is related suppressive agents, corticosteroid-induced interference with to defciencies in enzymatic killing of engulfed microorgan- phagocytic function, decreased neutrophils through antineu- isms. Examples of the intrinsic disorders include chronic trophil autoantibody; and abnormal neutrophil chemotaxis granulomatous disease, myeloperoxidase defciency, and glu- as a consequence of complement defciency or abnormal cose-6-phosphate dehydrogenase defciency. Intrinsic phagocytic dysfunction is of phagocytic dysfunction include increased susceptibility to related to defciencies in enzymatic defciencies that partici- bacterial infections but not to viral or protozoal infections. Selected phagocytic function disorders may be associated These intrinsic disorders include chronic granulomatous dis- with severe fungal infections. Severe bacterial infections ease, characterized by defects in the respiratory burst path- associated with phagocytic dysfunction range from mild skin way, myeloperoxidase defciency, and glucose-6-phosphate infections to fatal systemic infections. Consequences of phago- cytic dysfunction include increased susceptibility to bacterial Chemotaxis is the process whereby chemical substances infections but not to viral or protozoal infections. The orientation and phagocytic function disorders may be associated with severe movement of cells in the direction of a chemical’s concen- fungal infections. Severe bacterial infections associated with tration gradient is positive chemotaxis, whereas movement phagocytic dysfunction range from mild skin infections to away from the concentration gradient is termed negative fatal systemic infections. Substances that induce chemotaxis are referred to as chemotaxins and are often small molecules, such as Phagocytosis may involve nonimmunologic or immunologic C5a, formyl peptides, lymphokines, bacterial products, leu- mechanisms. These particles that have been modifed by chemical treatment or cells move into infammatory agents by chemotaxis. Damaged cells are also phagocytized by chamber device called a Boyden chamber is used to mea- nonimmunologic mechanisms. Damaged cells may become sure chemotaxis, in which phagocytic cells in culture are coated with immunoglobulin or other proteins which facili- separated from a chemotactic substance by a membrane. After attachment, the particle is engulfed within a membrane fragment and a Chemotaxis is locomotion of cells that may be stimulated phagocytic vacuole is formed. The vacuole fuses with the by the presence of certain substances in their environment. Remnants of indigestible material can be recog- cause/effect relationship between stimulus and response. The lat- an important role in defending the host against microbial ter form of cell movement is called chemotaxis and may be infection. These chemotactic factors are powerful Substances that may stimulate random cell locomotion are attractants for phagocytic cells which have specifc mem- called cytotoxigens; those that stimulate directed migration brane receptors for the factors. The main ele- be destroyed soon after phagocytosis as a result of oxidative ment in the effect of chemotactic factors is the presence of a reactions. However, certain intracellular microorganisms concentration gradient that determines the direction of cell 724 Atlas of Immunology, Third Edition migration. Under these circumstances a chemotactic signal the clinical relevance of this process is illustrated by chronic is provided to the cells under consideration. Hydrogen peroxide together with myeloper- mally in neurons of the human brain and is thought to be oxidase transforms chloride ions into hypochlorous ions involved in synaptic transmission. Immunologic memory is not involved, as previous other antimicrobial substances (Figure 24. The cells are also called large gran- bial cell death by an oxygen-independent mechanism. In the presence of a catalyst superoxide dismutase, against spontaneously developing neoplastic cells and against superoxidase ion is converted to hydrogen peroxide. It does not require granules that contain perforin or C9-related protein which sensitization and cannot be enhanced by specifc antigens. Other nonmemory cells include polymorphonuclear leuko- cytes and macrophages (Figure 24. They are involved in a and lymphocyte products suggest that surface adherent particular form of immune response, the antibody-dependent leukocytes undergo a large prolonged respiratory burst. Studies on regulation of neutrophil activation by plate- through its Fc region to the K cell’s Fc receptor. Intracellular Ca++ increases upregulation of ligand- releases lymphokines that destroy the target. Besides K cells, other cells that mediate activates downregulation of these receptors. Investigations of storage sites for the sev- Fab regions to target cell surface antigens. Following link- eral protein receptors have revealed a mobile intracellular age of Fc receptors with Fc regions, destruction of the target storage compartment in human neutrophils. It represents an stimuli, such as f-Met-Leu-Phe, may cause translocation of example of participation between antibody molecules and granules acting as storage sites to the cell surface, which immune system cells to produce an effector function. Humans have innate immunity against extracellular Dephosphorylation pathways for inositol triphosphate isomers bacteria. Both Ca++ and protein kinase C play a key role sis and digestion in phagocytic cells is a principal feature of in the activated pathway. Complement activation represents a signifcant fest an elevated expression of complement decay-accelerating mechanism for ridding the body of invading microorgan- factor, which protects erythrocytes from injury by autologous isms. Tumor cell Surface adherent leukocytes undergo a large prolonged respi- lysis ratory burst. The C3b that results from activation of enteric bacteria that are motile and Gram-negative. H is from complement serves as an opsonin when linked to the bac- the German word hauch, which means breath, and refers to terial surface, making the bacterial cell more attractive to the production of a flm on agar plates that resembles breath- phagocytes. Phase variation may result in a switch to pro- duction of the other type that is genetically controlled. O antigens of Shigella per- activate nonspecifc infammation and facilitate lymphocyte mit them to be subdivided into 40 serotypes. These infammatory cells migrate, accumulate in local areas, and become activated, enabling them to destroy the microorganisms. Flagellin is a protein that is a principal constituent of bac- Fever and the formation of acute-phase reactants may also be terial fagella. Some cytokines may facili- are arranged into helical chains which wind around a central tate specifc immune mechanisms by stimulating both T and hollow core. Mutations may occur in the central part of a sequelae during infection by extracellular microorganisms. It may produce endotoxin or hemorrhagic shock and modify resistance against infection. Endotoxins comprise an integral constituent of the outer membrane of Cell differentiation factors Alpha interferon Gram-negative microorganisms. Cytokines induced by endotoxins Hydrolytic enzymes Complement components cause fever, increased capillary permeability, and possible Collagenase C1 to C5 endotoxic shock. Relatively large amounts of lipopolysac- Lipase Properdin charide released from Gram-negative bacteria during Gram- Phosphatase Factors B, D, I, H negative septicemia may produce endotoxin shock. Endotoxin antigenicity, disguise, host molecule mimicry, surface anti- shock is also referred to as septic shock. Reducing An enterotoxin is a bacterial toxin that is heat stable and surface antigenicity by host molecule masking, shedding, or causes intestinal injury.
Helium–oxygen mixtures in intubated patients with status asthmaticus and respiratory acidosis cheap zocor 20 mg cholesterol medication does not affect liver. Mechanical ventilation: American College of Chest Physicians’ consensus conference generic zocor 20mg with amex cholesterol total. Pulmonary edema is often life-threatening purchase zocor 10 mg with mastercard list of cholesterol lowering foods diet, but effective therapy can rescue patients from its deleterious consequences. This article will discuss in brief the basic physiological principles that govern fluid filtration in the lungs, pathophysiology of pulmonary edema, diagnosis, treatment, and outcome of pulmonary edema and acute lung injury. The vascular compartment is separated from the interstitium by capillary endothelial cells. The interstitial compartment: the importance of this space lies in its interposition between the alveolar and vascular compartments. As fluid leaves the vascular compartment it collects in the interstitium before overflowing into the air spaces of the alveolar compartment. The alveolar compartment: This compartment is lined with type 1 and type 2 epithelial cells. Excess fluid present within the alveolar and interstitial compartments is drained via the lymphatic system. When the capacity for drainage of the lymphatics is surpassed, fluid accumulation occurs. Pulmonary edema occurs when fluid is filtered into the lungs faster than it can be removed. This in turn impedes efficient gas exchange which cannot occur in fluid-filled alveoli. The balance of driving forces normally causes filtration out of the bloodstream and there is usually a net outward flux of fluid and protein crossing from the vascular space into the interstitium. Because of the vast surface area of the lungs, most fluid and protein exchange in the lungs occurs across the interconnecting network of capillaries embedded in the alveolar walls. However, fluid exchange can also occur across capillaries located in the interstitium at alveolar wall junctions and also across small interstitial arteries and veins. Net movement of fluid across the alveolar-capillary membrane is expressed in the Starling equation: Q= k[ (Pc - Pi) - σ (Posmc – Posmi)] where Q is the net fluid-filtration rate (volume flow) across the microvascular barrier; k is the filtration coefficient (which is determined by permeability and surface area of the membrane), Pc and Pi are hydrostatic pressures in the capillary and interstitium respectively, σ is the osmotic reflection coefficient and Posmc and Posmi are the oncotic pressures in the capillary and interstitium. According to the Starling equation, the balance between the prevailing transmural hydrostatic pressures (Pc - Pi) and the colloid osmotic pressures (Posmc – Posmi) provides the “driving force” for filtration. Therefore the equation predicts the development of two fundamentally different kinds of pulmonary edema: increased pressure pulmonary edema, occurs when the driving forces increase, forcing fluid across the barrier at a rate that cannot be handled by lymphatic drainage; and the second, increased permeability pulmonary edema, which occurs in the presence of acute lung injury that damages the normal barriers to fluid filtration. The first kind is often referred to as cardiogenic and the second kind non-cardiogenic. There are protective factors that prevent pulmonary edema in the normal lung noted below. Increased Pressure Edema Also known as cardiogenic, high-pressure, hydrostatic, or secondary pulmonary edema. The flow of fluid and protein into the lungs increases when the sum of driving pressures is elevated. If the rate of fluid accumulation exceeds the rate at which it can be removed, increased pressure edema occurs. Some unique situations where pulmonary edema occurs due to more than one mechanism include high altitude pulmonary edema (increased hydrostatic pressure–pulmonary hypertension and increased permeability)7 and neurogenic pulmonary edema (increased pulmonary blood flow and increased permeability). Increased Permeability Edema (and Acute Lung Injury)10-12 Accumulation of fluid and protein increases when the lung endothelial and epithelial barriers are injured. If the rate of fluid accumulation exceeds the rate at which it can be removed, increased permeability edema occurs. Because the barriers limiting fluid and protein flow into the lungs do not function normally when the lungs are injured, the lungs are not protected against edema by the usual safety factors. This type of edema is more challenging to treat and requires a multisystem approach. The causes (mechanisms) of increased permeability pulmonary edema are summarized in Table 10. Direct insult by bacterial/ other infectious organisms, inflammation, changes in mechanical properties, destruction of surfactant, influx of cytokines/chemokines, release toxic oxygen metabolites, disturbance of normal cardio- pulmonary interactions, platelet/other microaggregation and other mechanisms have been proposed. Wheezing may be heard and may present a problem in differential diagnosis (“cardiac asthma”). Older children, especially with insidious onset pulmonary edema, may complain only of vague fatigue, mild pedal edema during the day, or exertional or paroxysmal nocturnal dyspnea. Patients with alveolar edema usually have severe dyspnea, tachypnea, and a productive cough that is often frothy and sometimes blood-tinged. Crackles and rhonchi may be heard, though the classic “fine” crackles may be difficult to appreciate in a child. However, in increased permeability edema, alveolar flooding can occur rapidly and the onset of symptoms may be sudden (“flash pulmonary edema”). Since pulmonary edema is usually due to an underlying pathology, signs of the primary condition should be identified so appropriate therapy can be instituted. Since increased pressure edema is usually caused by cardiac failure, there may be a history of heart disease. There may be signs and symptoms of any of the causes of chronic or acute congestive heart failure, such as hypertension, valvular heart disease, and severe volume expansion. History and physical examination may help differentiate increased permeability edema from increased pressure edema and identify a possible cause of acute lung injury. Because infection and the sepsis syndrome are major causes of acute lung injury, a thorough search must be made for signs and symptoms of an infectious cause. Note that many patients with acute lung injury may be febrile, whether or not an infection is clinically apparent. Diagnostic Studies and Definitions These are directed at establishing etiology in most cases. Appropriate cultures for microorganisms and toxicology screens of blood and urine are useful in identifying underlying causes of acute lung injuries. Sputum or tracheal aspirate examination, bronchoscopy with bronchoalveolar lavage (with quantitative cultures, if available) are all useful in diagnosing pneumonia in ventilated patients, even those who are being treated with antimicrobial drugs. Other tests including electrolytes, other metabolic parameters, hematologic tests, etc. As discussed previously, most causes of non-cardiogenic pulmonary edema (usually due to increased permeability) is due to acute lung injury. The most accepted criteria are those of the American-European Consensus Conference Definition (Table 10. It is difficult to correlate clinical signs or blood gas values to the actual structural damage to the capillary barrier. On the other hand there may be disorders which do cause structural damage, but do not affect oxygenation as much (e.
No retigabine-related efects on reproductive function were observed in male or female rats  order discount zocor cholesterol medication frequent urination. No teratogenic efects of reti- 10 mV –68 gabine were detected in rats and rabbits at a dose of 60 40mg zocor visa cholesterol binding medication. Perinatal and postnatal administration of retigabine to mat- 10 ms ed female rats was not associated with developmental toxicity in ofspring except delayed growth at the highest dose level (61 generic 40mg zocor visa cost of cholesterol test. Control Linopirdine Retigabine 15 min 30 min Pharmacokinetics Absorption 10 mV Retigabine is rapidly absorbed from the gastrointestinal tract, with –66 peak serum concentrations achieved within 0. A similar profle is observed at steady state in patients with epilepsy receiving 100–1200 mg/day (twice Figure 46. Over the therapeutic dosage range of 600–1200 mg/ permission from Society for NeuroScience. When retigabine is taken with a high-fat meal, Cmax atinine clearance of <30 mL/min) renal impairment or end-stage is modestly increased compared with administration in the fasted renal disease requiring dialysis . Whereas mild hepatic impairment did not alter Distribution the pharmacokinetics of a single 100-mg dose of retigabine, moder- The volume of distribution at steady state of retigabine, calculated ate and severe hepatic impairment resulted in 50% and 100% higher afer intravenous dosing, is about 2–3 L/kg. Plasma protein binding is re- Population pharmacokinetic analysis of data from healthy vol- versible and independent of plasma concentration (0. Retigabine is cleared partly by renal excretion in unchanged form and partly by metabolic elimination. About 20–30% of an orally administered radiolabelled dose is recovered in the urine as un- Drug interactions changed parent drug, and another 50–65% as metabolites. Metabolism is almost exclusively by hydrolysis/N-acetylation and glucuronidation . A major me- Studies in vitro tabolite in humans is an N-acetyl derivative that has weak pharma- In human liver microsomal assays, neither lamotrigine nor imipra- cological efects and inconsistent antiseizure activity in preclinical mine afected retigabine glucuronidation by human liver micro- models. Uridine diphosphate glucuronosyltransferase isozymes somes, even at very high concentrations . Retigabine does not induce or inhibit its own metabolism and pharmacokinetic profles afer multiple dose Studies in vivo (15 days) can be predicted from single-dose pharmacokinetics. Najjar type 2 syndrome) still produced glucuronide conjugates In a study designed to evaluate the pharmacokinetics of retiga- of retigabine . Taken together, these studies ic acid (n = 4) nor topiramate (n = 5) signifcantly altered retigabine suggest the existence of alternative routes of retigabine metabo- pharmacokinetics. A study in healthy young volunteers (18–40 years) and older sub- jects (66–81 years) evaluated the efect of old age and gender on Effect of retigabine on pharmacokinetics of other drugs the pharmacokinetics of retigabine administered as a single 200-mg dose . Median seizure frequency Studies in vivo was reduced by 23%, 29% and 35% from baseline in the groups In a study conducted in 15 healthy volunteers, treatment with reti- assigned to 600, 900 and 1200 mg/day retigabine, respectively, gabine at a dosage of 600 mg/day for 15 days was associated with a compared with a 13% reduction in the placebo group (P <0. Because of its modest magnitude, the interaction Phase 3 studies of retigabine with lamotrigine is unlikely to be clinically signifcant Two randomized double-blind placebo-controlled adjunctive- in the majority of patients. Tese fndings suggest no potential was followed by a 4-week transition phase for those enrolling in for reduced contraceptive efcacy when retigabine is added on to open-label extension trials. Tose unable to achieve the target dose or unable exposure was similar to that in other studies, suggesting that con- to tolerate the single dose reduction discontinued the study. Patient characteristics at baseline were very similar across the Clinical effcacy two studies. During double-blind treatment, retigabine at all three The phase 2b study (Study 205)  was a dose-ranging trial doses signifcantly reduced median seizure frequency compared evaluating 600, 900 and 1200 mg/day retigabine administered three with placebo [74,75]. Efcacy was clearly dose-related in terms of times a day versus placebo as adjunctive therapy. The study consisted of an 8-week baseline patients who were seizure-free for the entire 12-week maintenance phase, 8-week forced titration phase and an 8-week maintenance period was signifcantly superior to placebo for the 1200-mg dos- phase. Only two 100-mg dose decrements were allowed during Long-term open label extension trials weeks 7 and 8; minimum dosages during the 8-week maintenance The open-label extension from Study 205, Study 212, involved 80% phase were 400, 700 and 1000 mg/day. Enrolled patients were on of patients who completed the maintenance period (222out of 279) 612 Chapter 46 Table 46. Retigabine Outcome/population/study Placebo 600 mg/day 900 mg/day 1200 mg/day Median percentage reduction from baseline in 28-day total focal seizure frequency Population: double-blind period: Studies 205-302 14. Continuous 6-month and 12-month sei- 26% of patients discontinued due to inadequate seizure control and zure-free rates for retigabine exposures ≥12 months were 13. At the end of open-label treatment, 78% were receiving ≤900 mg/day and the optimized dose was ≥1200 mg/day in only Studies in patients with other disorders 10% of patients (maximum dosage, 1500 mg/day). A placebo-controlled (Study 304) and 6-week (Study 303) double-blind transition phase proof-of-concept study that had been initiated in patients with pos- to target doses of 900 and 1200 mg/day, respectively. Lower doses of therpetic neuralgia did not meet its pre-specifed primary efcacy 600 mg/day (Study 304) or 900 mg/day (Study 303) were acceptable end-point. If retigabine was discontinued, forced titration and very little dosing fexibility to reduce common a 3-week tapering period was used. At than two-thirds of discontinuations occurred during forced titra- data cut-of, 336 (60%) patients received ≥12 months’ open-label tion. From baseline to data cut-of, a median reduction of tinuation were dizziness (6%), fatigue (4%), somnolence (4%) and 53% (10. Retigabine (mg/day) Placebo 600 900 1200 (n = 331) (n = 181) ( = 178) (n = 153) Dizziness 9 17 26 40 Somnolence 13 14 26 31 Fatigue 5 17 15 16 Confusion 1 2 5 14 Dysarthria 1 5 2 12 Headache 16 11 17 12 (a) Ataxia/gait 4 3 5 12 disturbance Urinary tract 5 1 2 12 infection Tremor 3 2 8 11 Blurred vision 2 1 5 11 Nausea 5 6 7 11 two deaths (0. Retigabine, as a potassium channel opener, infuences the reac- tivity of the smooth muscle of the urinary bladder. Consequently, its information, approximately 10% of patients in long-term clinical adverse event profle includes efects on the urinary system. In the trials developed skin discoloration, generally afer 2 or more years pivotal controlled trials and the overall phase 2–3 clinical develop- of treatment and at higher doses (≥900 mg) . However, most patients presenting with vision, although this was mild in all but one patient. One patient quences, reversibility, time to onset and pathophysiology of the only receiving retigabine (600 mg/day) needed catheterization due retinal and skin abnormalities remain to be determined. Potential secondary renal efects, which may be caused fessional and follow-up testing every 6 months. Additional testing includes fuorescein angiograms, currence of discoloration of the skin which appeared as blue pig- ocular coherence tomography, perimetry and electroretinograms. The mechanisms of the pigment changes, the magnitude generally reached a plateau during open-label treatment . Until these during pregnancy or by nursing women only if the potential beneft knowledge gaps are adequately addressed, it is unlikely that current outweighs the potential risk for the fetus or the infant. Current place in therapy Clinical studies have documented the efcacy of retigabine as ad- References junctive therapy in adults with refractory focal seizures. Anticonvulsant properties of D-20443 in stages of the medical management of localization-related epilepsies, genetically epilepsy-prone rats: prediction of clinical response.
J. Dudley. Northern Illinois University.