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Sources of toxic substances are anti- oxidants order provera 10 mg line, catalysts discount provera 5 mg visa, and contaminants from fabrication equipment generic 2.5mg provera mastercard. Microfabricated electrodes were initially conceived in the early 1970s (Wise et al discount provera 2.5mg mastercard. In subsequent years order provera 10mg free shipping, the dimensions of these electrodes have been decreased, using concurrent advances in the microelectronics industry. Today, micromachined silicon electrodes with conducting lines of 2 mm are standard (Hetke et al. Long-term implantation and in vitro testing have demonstrated the ability of silicon devices to maintain electrical charac- teristics for long-periods (Weiland and Anderson, 2000). Using simple waveforms, conservative charge density limits for long-term stimulation with plati- num are 100 mC/cm2. For activated iridium oxide electrodes, the limit is 1 mC/cm2 (Beebe and Rose, 1988). Platinum-iridium alloys are mechanically stronger then plat- inum alone. Most neural prostheses use platinum stimulating electrodes, the exception being the BION microstimulator (Advanced Bionics, Sylmar, California), which uses iridium oxide. Iridium oxide has been shown in vitro to have a safe stimulation limit of 3 mC/cm2 (Beebe and Rose, 1988). Recently, a titanium nitride, thin-ﬁlm electrode has demonstrated charge in- jection limits higher than both platinum and iridium oxide, with an in vitro limit of 22 mC/cm2 (Janders et al. Stabilizing the electrode array on the surface of the retina is an especially formida- ble problem. The biocompatibility and the feasibility of surgically implanting an elec- trode array onto the retinal surface have been examined at Johns Hopkins University Hospital. In one experiment, a 5 Â 5 electrode array (25 disk-shaped platinum elec- trodes in a silicone matrix) was implanted on the retinal surface using retinal tacks in each of four mixed-breed sighted dogs for a maximum period of 1 year. No retinal Stimulation of Large Retinal Tissue Areas 29 detachment, infection, or uncontrolled intraocular bleeding occurred in any of the animals. Retinal tacks and the retinal array remained ﬁrmly a‰xed to the retina throughout the follow-up period. It was concluded that implantation of an electrode array on the epiretinal side (i. Another method for attaching electrode arrays is by biocompatible adhesives. Nine commercially available compounds were examined for their suitability as intraocular adhesives: commercial ﬁbrin sealant, autologous ﬁbrin, Cell-Tak, three photocurable glues, and three di¤erent polyethylene glycol hydrogels. Hydrogels proved superior for intraocular use in terms of consistency, adhesiveness, stability, impermeability, and safety. IRP Experiments A number of in vivo and in vitro retinal stimulation studies have been performed in animals and humans at Johns Hopkins University Hospital. The next major step will be long-term implantation of active devices in animal models to examine the e‰cacy and safety of such devices. Speciﬁc parameters that will be examined during these experiments are the clinical appearance of the retina during the period of the implantation, and electrophysiolog- ical responses—electroretinogram (ERG) and visual-evoked potentials (VEP). The VEP can be examined by scalp electrodes, subdural surface electrodes, or intracorti- cal recording of single neurons. These experiments will be conducted in both normal and retinal degenerate animals. After chronic implantation in animal models, the ret- ina and cortex will be examined for any histological damage using optical and elec- tron microscopy. If animal model experiments prove successful, chronic human experiments would follow with blind volunteer patients. Future devices will contain more electrodes, more advanced electronics, and radio- frequency or other wireless communication links. After successful demonstration of prototype devices, the issues of biocompatibilty will become the most challenging aspect of this technology. Research programs to develop retinal and cortical visual prostheses are progress- ing in parallel tracks, and it is too early to say if either will provide therapeutic ben- eﬁt. Chronic experiments in animal models and humans will provide some idea of the future of these projects in 5 years. A successful retinal prosthetic device will aid only blind patients a¤ected with outer retinal degenerative diseases such as RP and AMD. It is not clear whether humans who became blind early in life will beneﬁt from either type of pros- thesis.
For these trials discount 10 mg provera with mastercard, the primary endpoints survival analysis allows for comparison of the consisted of a cognitive measure to determine entire group despite varying lengths of follow-up cheap provera 5mg on-line, the speciﬁcity of the agent on important cogni- i generic 10mg provera fast delivery. Fifth buy 10mg provera with mastercard, it is usually more infor- tive endpoints and a clinical global impression mative unless the incidence is low buy provera 10 mg with mastercard. The potential to make certain that the overall effect was suf- disadvantage of survival analysis in AD trials is ﬁciently robust to be clinically signiﬁcant. Trials that the time to reach certain endpoints (such as examining agents designed to alter the rate of institutionalisation) is likely to be more variable decline have generally used a difference in slope and affected by social support systems than the or a difference at endpoint in cognitive and global rate of change on a cognitive measure. One recent trial used the time to devel- large numbers of patients drop out of the study opment of functional endpoints such as insti- without reaching the deﬁned study endpoint, the tutionalisation, death, loss of activities of daily validity of the study may be open to question. PHASE 1 TRIALS SURVIVAL ANALYSIS IN AD Phase 1 trials for AD are carried out to deter- mine the general tolerability of the agent and While the use of endpoint differences and maximum tolerated dose. These trials commonly changes in the rate of decline are currently the utilise fewer than 100 subjects exposed to drug. Subsequently, the tolerability of multiple daily First, endpoints can be real-life events rather than doses is evaluated in brief trials lasting for artiﬁcial constructs such as the amount of change one to two weeks. Events such as death and ing multiple daily dosing have been carried out institutionalisation require little interpretation and in early AD patients rather than normal con- clearly possess face validity. The advan- analysis naturally allows the combination of mul- tage of this approach is that if the metabolism tiple endpoints; also, any patient who reaches one of the drug differs between AD patients and 248 TEXTBOOK OF CLINICAL TRIALS healthy normal controls, the doses tolerated by Few phase 2 trials are designed to examine the AD patients will be found early in the drug ability of the agent to slow decline in AD. Early phase 1 studies focus efﬁcacy-oriented studies are infrequently carried on tolerability, side effects and pharmacokinet- out because of the need for a large sample size ics. In general, studies designed to out to look for food interactions and interac- slow decline are carried out in phase 3 clinical tions with other commonly used pharmaceuti- trials. For PHASE 2 TRIALS one-year trials designed to slow decline in AD, using a typical outcome measure in which the Phase 2 trials are classically designed to explore standard deviation of the rate of change is equal the dose range of an agent and to establish an to the one-year decline, a typical study using initial determination of efﬁcacy. They generally 80% power and two-sided testing with an alpha utilise 100–500 subjects. Due to the time and (type 1 error) of 5% would require 63 subjects cost involved in the drug development process, per group (assuming no drop-outs) comparing many sponsors are currently carrying out com- drug to placebo for signiﬁcance to detect a 50% bined phase 2/3 studies. Most are carried out as multi-arm, parallel, placebo- studies are powered to detect 25–40% decreases controlled trials. The maximum dose used in such in rate of decline and therefore require larger a trial is approximately one-half to two-thirds sample sizes. Two, three or four doses are generally employed and compared to placebo. In PHASE 3 TRIALS some trial designs, an arm of an already-approved agent may be added as a positive control. Most Many AD trials are currently carried out as com- phase 2 trials designed for symptomatic treatment bined phase 2/3 studies. Depending on the num- are approximately six months in duration in order ber of arms, these trials generally utilise 300–600 to meet both European and US regulatory guide- subjects per trial. For short-term trials designed to efﬁcacy in clinical trials with continuous response improve cognition, three trial designs have been measures depends on the relationship between the used: crossover designs, randomised control par- effect size sought, the standard deviation of the allel designs (RCPD) and enrichment designs outcome measure, and other parameters such as type 1 error, type 2 error, drop-out rate, drop- Table 16. Same size calculations for AD slope trial in rate, and base rate for the control group. For example, for a treatment trial seeking to detect Reduction in rate Subjects per Total sample a four-point difference on the ADAS-Cog at six of decline (%) group (N) size (N) months assuming a standard deviation of nine, 25 251 502 100 subjects per group would be required in a 50 63 126 two-arm trial with a power of 90% and an alpha 75 28 56 (type 1 error) of 5%. The use of the used neuropsychological instruments, the annual crossover design presents a number of problems rate of change is approximately equal to the one- for the study of AD patients. Thus, for the that there are no carry-over or period effects of ADAS-Cog, the rate of change is approximately the drug and that the treatment response is the 7. The rate of change studies indicates that the rate of major advantage of this design is in the economy decline on common instruments is reasonably of subjects because each subject acts as its own constant during the middle stages of dementia but control. However, because AD is not a static dis- is slower in early and more severe dementia. Randomised, controlled, par- decline is likely to be inﬂuenced by the distribu- allel design studies have two major advantages: tion of disease subtypes such as the presence of the control population is concurrent (thus any the Lewy body variant of AD. It was used in sev- rary phase 3 studies examining rate of decline in eral cholinesterase inhibitor trials including one AD are designed to detect group differences of of the US multicentre tacrine trials. Non-responders were dropped from in AD, one trial of vitamin E and selegiline16 the trial prior to the double-blind phase, thereby utilised survival analysis in a 2 × 2 factorial resulting in enrollment of an enriched popula- design to examine the time to important endpoints tion in the double-blind phase. One advantage of the 2 × has many advantages including individual dose 2 factorial design is that two agents can be titration for each patient, its major disadvan- tested simultaneously. In addition, interactions tage is that all subjects are exposed to drug at between the two agents can be examined.
If progressive renal impairment be- potassium or spironolactone may be needed provera 10mg low cost. Metolazone and indapamide are thiazide-related di- Fast-acting generic provera 2.5mg overnight delivery, potent diuretics such as furosemide and bume- uretics that may be effective in clients with significantly im- tanide are the most likely diuretics to be used in critically ill paired renal function provera 5mg visa. In clients with se- Loop diuretics are effective in clients with renal impair- vere renal impairment buy provera 10 mg online, high doses are required to produce di- ment cheap 10 mg provera with amex. Large doses may produce ﬂuid volume depletion and peak concentrations at their site of action, which decreases worsen renal function. If high doses of furosemide are used, a volume-controlled IV infusion at a rate of 4 mg/minute or Home Care less may be used. If IV bumetanide is given to clients with chronic renal impairment, a continuous infusion (eg, 12 mg Diuretics are often taken in the home setting. The home care over 12 hours) produces more diuresis than equivalent-dose nurse may need to assist clients and caregivers in using the intermittent injections. Continuous infusion also produces drugs safely and effectively, monitor client responses (eg, as- lower serum drug levels and therefore may decrease adverse sess nutritional status, blood pressure, weight, and use of effects. If they are used at all, frequent monitoring of serum to assist the client in obtaining medications or blood tests electrolytes, creatinine, and BUN is needed. So that peak action will occur during waking hours and not inter- fere with sleep b. Keep the call light within reach, and be sure the client knows how to use it. Assist to the bathroom anyone who is elderly, weak, dizzy, or unsteady in walking. Give amiloride and triamterene with or after food To decrease gastrointestinal (GI) upset d. Give intravenous (IV) injections of furosemide and To decrease or avoid high peak serum levels, which increase risks bumetanide over 1–2 min; give torsemide over 2 min. Give high-dose furosemide continuous IV infusions at a rate of 4 mg/min or less (continued) CHAPTER 56 DIURETICS 829 NURSING ACTIONS RATIONALE/EXPLANATION 2. Decrease or absence of edema, increased urine output, de- Most oral diuretics act within 2 h; IV diuretics act within minutes. Also, weighing assists in dosage regulation to maintain nation, with the same amount of clothing, and using the therapeutic beneﬁt without excessive or too rapid ﬂuid loss. With diuretic therapy, urinary output may exceed intake, de- pending on the amount of edema or ﬂuid retention, renal function, and diuretic dosage. All sources of ﬂuid gain, including IV ﬂuids, must be included; all sources of ﬂuid loss (perspiration, fever, wound drainage, GI tract drainage) are important. Clients with ab- normal ﬂuid losses have less urine output with diuretic therapy. Output greater than 100 mL/h may indicate that side effects are more likely to occur. Dilute urine may indicate excessive ﬂuid intake or greater likeli- hood of ﬂuid and electrolyte imbalance due to rapid diuresis. If kles for the ambulatory client, sacral area and posterior edema reappears or worsens, a thorough reassessment of the client thighs for clients at bed rest. Questions to be answered include: sure abdominal girth, ankles, and calves to monitor gain or (1) Is the prescribed diuretic being taken correctly? Observe for adverse effects Major adverse effects are ﬂuid and electrolyte imbalances. With potassium-losing diuretics (thiazides, bumetanide, furosemide, ethacrynic acid), observe for: (1) Hypokalemia Potassium is required for normal muscle function. Thus, potassium depletion causes weakness of cardiovascular, respiratory, digestive, (a) Serum potassium levels below 3. Clients most likely to have hypokalemia (b) Electrocardiographic (ECG) changes (eg, low volt- are those who are taking large doses of diuretics, potent diuretics age, ﬂattened T wave, depressed ST segment) (eg, furosemide), or adrenal corticosteroids; those who have de- (c) Cardiac dysrhythmias; weak, irregular pulse creased food and ﬂuid intake; or those who have increased potas- sium losses through vomiting, diarrhea, chronic laxative or enema (d) Hypotension use, or GI suction. Clinically signiﬁcant symptoms are most likely (e) Weak, shallow respirations to occur with a serum potassium level below 3 mEq/L. Furosemide and other loop diuretics tend to cause hypocalcemia and hypercalciuria.
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