Keppra

By P. Goose. State University of New York College at Farmingdale.

One of the unique characteristics of 1) buy keppra 250mg mastercard, all of which are homologs of human regulatory genes cheap 250 mg keppra with amex. Lytic this virus is its expression of viral homologs of human regulatory 2 virus expression is most common in MCD, less so in KS, and proteins such as cyclin D, IL-6, bcl-2, and others. Although the expression of lytic cycle genes in largely latent in B cells, neoplastic KS spindle cells, and some the 3 diseases discussed here may differ, there are certainly atypical endothelial cells in KS. Lytic infection occurs in 3% KS 3 commonalities that can be related to the clinical characteristics of cells and is more frequent in MCD. The unique role of HHV8 in the pathogenesis of each of the 3 malignancies is discussed below (Figure 2). Latent gene expression HHV8 latent genes expressed include latency associated nuclear KS. HHV8 is required for the development of KS and the virus is antigen (LANA-1), v-FLIP (a viral analog of the FLICE inhibitory found in all subtypes of the disease, including classical, endemic, protein), and v-cyclin, all expressed off of the LANA promoter; and epidemic (HIV-associated), and posttransplantation KS. KS lesions Kaposin B (for review, see Schulz4 and Fukumoto5). Latent gene are characterized by the presence of neoangiogenesis. Cultured cells expression is present in all 3 disorders and centers around the ability transfected with v-GPCR up-regulate VEGF and bFGF,6 factors that of these proteins to promote cell cycle progression and inhibit play key roles in the pathogenesis of KS. Expression of v-GPCR in apoptosis, whether in KS spindle cells or B cells associated with transgenic mice produces angioproliferative lesions that resemble MCD or PEL. Furthermore, HHV8 infection in- LANA-1, which binds the tumor suppressor Rb, leading to en- duces c-kit gene expression in dermal microvascular endothelial hanced expression of E2F, and by expression of v-cyclin, which cells, transforming them from a cobblestone-like monolayer to binds to and activates cdk6 (Figure 2). Genome diagram of KSHV and viral transcripts expressed in KS, PEL, and MCD. There are more than 90 genes in the viral genome, but this diagram only shows those mentioned in this review. The arrows underneath the genome indicate the transcripts expressed in virus-infected cells in the 3 pathologies associated with KSHV. As discussed in the text, the majority of cells are latently infected in KS, PEL, and MCD, whereas there is a higher rate of lytically infected cells in MCD than in KS or PEL. Also known as “angiofollicular hyperplasia,” MCD is most HHV8 infection also up-regulates mRNA expression of multiple commonly observed in HIV patients and transplantation recipients, matrix metalloproteinases. PEL is characterized as an aggressive lymphoma presenting sion is broad in MCD, indicating a much stronger component of with malignant pleural, pericardial, or peritoneal effusions in the lytic infection than in either PEL or KS. V-IL6 is expressed in many absence of a discrete tumor mass. The cells are of B-cell origin, of the LANA-positive cells, is frequently detected in blood, and is although they rarely express CD20. Expression of CD38 and 138 believed to be a key factor responsible for B-cell proliferation. The pattern of gene expression is role in enhancing cytokine expression, with VEGF again playing an predominantly latent. Most cells express LANA, v-cyclin, v-FLIP, important role in the “angioproliferative” component, as is the case and kaposin. In addition, the classic form of KS occurring in Figure 2. Pathogenesis of the HHV8-associated diseases KS, PEL, and MCD. Shown is the pathogenesis of the HHV8-associated diseases KS, PEL, and MCD demonstrating viral effects on apoptosis, cell cycle progression, angiogenesis, cytokine production, and B-cell proliferation as described in the text. Targeted therapies in KS Drug Population Target N ORR Reference IFN- HIV with cART Angiogenesis immune modulation 13 38% 15 COL-3 HIV MMP inhibitor 37 41% 16 Imatinib HIV c-kit PDGF 10 50% 17 Imatinib HIV c-kit PDGF 30 33% 18 Lenalidomide HIV VEGF, immune modulation 3 100% 19 Sirolimus Posttransplantation Akt/mTOR 15 100% 20 IL-12 HIV Angiogenesis 24 71% 21 MMP,matrixmetalloprotein;andORR,overallresponserate. The lesions typically have a violaceous appearance and involve KS is present in up to 70% of individuals with MCD at diagnosis. The disease can be cosmetically disfigur- Laboratory abnormalities include anemia in most patients, poly- ing and, with extensive spread of the disease in the skin, may be clonal hypergammaglobulinemia, hypoalbuminemia, cytopenias, associated with lymphedema, pain, and secondary infection. Vis- respiratory symptoms, elevated C-reactive protein, and weight loss. Death due to KS and a polyneuropathy may occur with or without POEMS syn- is rare and can be associated with pulmonary involvement. The disease may take on a pattern of exacerbations with subsequent spontaneous remissions, whereas in others, a severe Localized, cosmetically unsightly lesions are most commonly acute illness may occur with a rapid downhill course. Localized radiotherapy is also an option for The diagnosis of MCD is based upon tissue biopsy, usually from a larger lesions, but doses should be kept low to avoid late complica- lymph node. The plasmacytic variant is most commonly observed in tions of therapy, such as sclerotic skin changes and chronic HIV patients and consists of hyperplastic follicles with indistinct lymphedema. These are most patients, demonstrating the beneficial effect of immune reconstitu- often polyclonal, but occasionally will progress to monoclonal tion. Studies to identify the presence of associated with initial progression of KS as a manifestation of an HHV8 either from tissue or peripheral blood should be performed. Immunohistochemical staining for LANA will identify the presence of HHV8 in 10% to 30% of lymphocytes in the mantle zone.

Discontinuation rates were higher among patients with schizophrenia than is typical in other diseases discount keppra 500mg online, with rates of 50% or more being common cheap keppra 500 mg with visa. As noted above, the Atypical antipsychotic drugs Page 46 of 230 Final Report Update 3 Drug Effectiveness Review Project CATIE study used this outcome as the primary measure of effectiveness along with time to discontinuation. Rate of discontinuation Data from discontinuation rates from 79 head-to-head trials were used in a mixed treatment comparisons analysis (also known as a network meta-analysis; Table 3). This analysis included data from all phases of the CATIE study. With 1493 patients enrolled in Phase 1, this study constituted the largest study among the 79 included in the analysis. The mixed treatment comparisons analysis used both direct and indirect comparisons based on the head-to-head trials and found that olanzapine was superior to aripiprazole, asenapine, iloperidone, immediate- release quetiapine, risperidone, and ziprasidone in rates of all-cause discontinuation of assigned drug across all the trials. Clozapine was found superior to iloperidone, immediate-release quetiapine, risperidone, and ziprasidone. Risperidone was also found superior to iloperidone, based on limited evidence. A difference between clozapine and olanzapine was not found. Statistically significant differences between paliperidone and other drugs were also not found, likely due to the very low numbers of studies with direct comparisons to other atypical antipsychotics. This analysis controlled for between-study heterogeneity, dose level within study (low, medium, or high), and study duration using the fixed-effects model. It did not control for within-study heterogeneity for those studies with more than 2 drug arms. Dose comparisons were an issue in this set of studies, with early studies using doses that were not considered clinically optimal now. For example, early studies of risperidone often used doses well above those used today and clozapine and olanzapine studies used doses below those used today. There were fewer comparative data available for the newer drugs, particularly asenapine, iloperidone, and paliperidone, and results for these drugs should be interpreted with caution. Sensitivity analyses stratifying studies by shorter and longer durations did not alter the results in meaningful ways. For example, the odds ratio for olanzapine compared with risperidone for studies 6 months or less (N=58) was 0. Atypical antipsychotic drugs Page 47 of 230 Final Report Update 3 Drug Effectiveness Review Project a Table 3. Mixed-treatment comparisons analysis of discontinuations from trials Asenapine Clozapine Iloperidone Olanzapine Quetiapine Paliperidone Risperidone Ziprasidone 1. Atypical antipsychotic drugs Page 48 of 230 Final Report Update 3 Drug Effectiveness Review Project For olanzapine, these results compared with the results of CATIE Phase 1 as shown in Table 4, below. In comparing olanzapine with ziprasidone, the mixed-treatment comparisons analysis found a larger magnitude of effect favoring olanzapine than CATIE found. In CATIE Phase 1, risperidone, immediate-release quetiapine, and ziprasidone were not statistically significantly different from each other. Olanzapine was also found to have lower rates of discontinuations due to lack of efficacy or patient decision, and significantly longer duration of successful treatment than immediate-release quetiapine. The numbers needed to treat with olanzapine for discontinuation due to lack of efficacy were 7. A statistically significant difference was not found between risperidone and quetiapine or between risperidone and ziprasidone for either lack of efficacy or due to the patient’s decision. Analyses of discontinuation rates of olanzapine compared with other atypical antipsychotic drugs Comparison CATIE Phase 1 Number Mixed-treatment Number atypical Hazard ratio needed comparisons needed antipsychotic (95% CI) to treat N Odds ratio (95% CI) to treat N Quetiapine 0. An analysis of 31 trials directly comparing olanzapine with risperidone is represented in Figure 4, below. The graph indicates that olanzapine had lower rates of early discontinuation of drug compared with risperidone. This group of studies represented the largest body of direct comparison evidence in this report. Atypical antipsychotic drugs Page 49 of 230 Final Report Update 3 Drug Effectiveness Review Project Figure 4. Relative risk of early discontinuation of olanzapine compared with risperidone (symbol size represents sample size) 100 Olanzapine % 75 50 25 0 0 25 50 75 100 Risperidone % Fourteen retrospective studies, utilizing databases of medical and/or prescription claims 156, 166, 169, 170, 175, 176, 180, 181, 185, 197, 203, 204, 210, 212 or electronic medical records and the European and 218, 247 Intercontinental SOHO studies (Table 5), reported comparative evidence on rate and/or 175 time to discontinuation of atypical antipsychotics. Overall, the findings of these studies were consistent with the trials in that clozapine was found to have lower discontinuation rates than other atypical antipsychotic drugs and olanzapine was found to have lower rates than the rest of the atypical antipsychotic drugs, with few exceptions. New evidence on risperidone long-acting injection indicated that oral atypical antipsychotics may have lower rates of discontinuation over longer periods of follow-up (18 months). Findings were also consistent that olanzapine resulted in a longer time to discontinuation compared with other antipsychotics, with the exception of clozapine. Clozapine was found to have a lower discontinuation rate than other atypical antipsychotics studied (olanzapine, immediate-release quetiapine, risperidone, risperidone long- 203, 212, 247 acting injection). Of 10 studies comparing olanzapine with risperidone, 6 found the rate 166, 169, 175, 176, 218, 247 of discontinuation lower with olanzapine, while the others did not find a 181, 197, 204, 212 statistically significant difference. Olanzapine was not found to have statistically significantly different rates of discontinuation compared with aripiprazole or ziprasidone in a 204 study of Maryland Medicaid data.

The difference was less than one awakening per night (mean difference -0 purchase 250 mg keppra with visa. Insomnia Page 24 of 86 Final Report Update 2 Drug Effectiveness Review Project Figure 5 order keppra 250 mg with visa. Subjective number of awakenings in placebo-controlled trials of newer insomnia drugs Review: Insomnia Drugs Manuscript July 2008 (Copy of insomnia) Comparison: 01 Newer insomnia drugs vs placebo Outcome: 05 Subjective number of awakenings Study Treatment Placebo WMD (random) WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI 01 Eszopiclone 2 mg vs placebo Zammit 2004 104 2. Data from varying doses of the same drug were combined for this indirect comparison. There were very few significant differences between the drugs on any outcomes. The exceptions were significantly shorter sleep latency and longer sleep duration with eszopiclone compared to ramelteon. On average, sleep latency was 11 minutes shorter with eszopiclone than ramelteon (95% CI -21 to -1. Sleep duration was an average of 37 minutes longer with eszopiclone than ramelteon (95% CI 17 to 56 minutes). Patients taking eszopiclone had significantly fewer awakenings than those taking zolpidem, but the difference was less than one time per night (mean difference 0. Insomnia Page 25 of 86 Final Report Update 2 Drug Effectiveness Review Project Table 6. Adjusted indirect meta-analysis: Summary of results Mean difference (95% confidence interval) Sleep latency Sleep duration Number of WASO in minutes in minutes awakenings in minutes Eszopiclone a -11. We performed several subgroup analyses to determine if meta-analysis results varied by population or study design characteristics. When studies conducted in adult and elderly patients were analyzed separately, adjusted indirect analysis showed no significant differences between any of the drugs in subjective sleep latency or WASO (Table 7). In elderly patients, sleep duration was significantly longer with eszopiclone than with ramelteon and zolpidem in elderly patients, but there was no difference between any of the drugs in adult patients under age 65. Insomnia Page 26 of 86 Final Report Update 2 Drug Effectiveness Review Project Table 7. Subgroup analysis by elderly and non-elderly adult patients Mean difference (95% confidence interval) Sleep latency Sleep duration Number of WASO in minutes in minutes awakenings in minutes Eszopiclone compared Adults -14. We also performed a subgroup analysis excluding studies that used doses other than the manufacturers’ recommended initial dose. Recommended initial doses are eszopiclone 2 mg, ramelteon 8 mg, zaleplon 10 mg, zolpidem 10 mg, and zopiclone 7. In fair-quality studies, eszopiclone significantly increased sleep duration compared with zolpidem (mean difference 37. PSG-measured outcomes in trials of ramelteon 77, PSG-measured sleep outcomes were reported in three placebo-controlled trials of ramelteon. The primary outcome, sleep latency at week 1 was reduced for both the 8 mg (32 minutes) and 16 mg (29 minutes) groups compared to placebo (48 minutes, P<0. Total sleep time was improved with ramelteon compared with placebo at weeks 1 and 3 but not week 5. There were no differences in WASO or number of awakenings. In a crossover study of 2 nights of treatment with ramelteon 4 mg, 8 mg, 16 mg, or 32 mg, all doses of ramelteon resulted in reductions in PSG-measured sleep latency (P<0. There were no differences in WASO for any of the treated groups compared to placebo. In a 2-night crossover study conducted in patients over age 65, there were significant improvements in PSG-measured sleep latency with ramelteon 4 mg (28. PSG-measured total sleep time was also improved with ramelteon (359 minutes for 4 mg and 362 minutes for 8 mg compared with 350 minutes for placebo; P=0. There was no difference in objective WASO with either dose of ramelteon compared to placebo, and there was an increase in number of awakenings with ramelteon 4 mg (but not with the 8 mg dose). Zolpidem extended-release There are no head-to-head trials comparing zolpidem extended-release with other newer drugs for insomnia. Evidence for the efficacy of zolpidem extended-release comes from three fair- 89, 115, 121 quality placebo-controlled trials. Additional information is provided in the FDA 79 statistical review of zolpidem extended-release Table 8 summarizes the results of these trials. Because they did not report means for subjective sleep outcomes at endpoint, we were not able to include their data in our meta-analysis. Insomnia Page 28 of 86 Final Report Update 2 Drug Effectiveness Review Project Table 8.

One study compared immediate-release formulations of trospium with oxybutynin buy keppra 500mg otc. Significant differences were not found for frequency of micturition cheap 250 mg keppra with visa, 34 incontinence, or urgency. No significant differences were found between drugs by intention-to- treat analysis in any study. Extended-release compared with extended-release 31 The OPERA trial randomized 790 patients to extended-release oxybutynin 10 mg daily or extended-release tolterodine 4 mg daily for 12 weeks. Forty-seven percent of patients had prior anticholinergic drug therapy for urge incontinence. There was no difference between the groups in the mean change in frequency of urge incontinence (–26. Also, no difference was found in mean change in total number of incontinence episodes. Differences were found in the proportion of patients with no incontinence (23% compared with 17%; P=0. This study was fair-quality and used the last-observation-carried- forward technique to conduct an intention-to-treat analysis on these efficacy measures. The other study comparing the 2 extended-release formulations did not report these 44 outcomes. A fair-quality systematic review evaluated differences in tolerability, safety, and efficacy 16 between oxybutynin and tolterodine extended release formulations. This review found that based on 1 short-term trial, oxybutynin extended-release caused a greater number of patients to return to continence and a greater mean reduction in incontinent episodes than tolterodine Overactive bladder Page 18 of 73 Final Report Update 4 Drug Effectiveness Review Project 31 extended-release. In contrast, we concluded, as did the original study, that there is no significant difference in mean reduction of number of incontinent episodes between oxybutynin extended-release and tolterodine extended-release. It appears that this 2005 review found this difference to be statistically significant using a per protocol analysis to calculate relative risk values. Transdermal compared with immediate-release A 6-week study comparing transdermal oxybutynin with immediate-release oxybutynin assigned the starting dose depending on the previous dose of oxybutynin (patients were required to have 30 been on oxybutynin for at least 6 weeks and to have had symptomatic improvement). Dose was then titrated to effect or to side effects over the 6-week study period. No significant differences were found in this small study in the percent change in mean number of incontinence episodes (66. Transdermal compared with extended-release One study randomized 361 patients to transdermal oxybutynin 3. All patients had been taking an anticholinergic drug for incontinence with symptomatic improvement prior to enrollment. The distribution of those taking oxybutynin (oral) and tolterodine prior to enrollment was about even in all groups. No significant differences were found between these drugs on the basis of mean change in number of incontinence episodes per day at 12 weeks (oxybutynin transdermal –2. Symptoms and overall assessment of benefit Immediate-release compared with immediate-release All 4 studies comparing immediate-release oxybutynin and immediate-release tolterodine 21, 49 reported success based on subjective patient assessments. Two studies used a 6-point scale of symptom severity (0 = no problems, 6 = severe problems). The proportion of patients improving by 1 point or more on this scale was reported in both studies. In the study comparing tolterodine 49 2 mg twice daily to oxybutynin 5 mg twice daily for 8 weeks, 45% reported improvement on tolterodine and 41% on oxybutynin. In the study comparing tolterodine 2 mg twice daily to 21 oxybutynin 5 mg 3 times daily, 50% of patients taking tolterodine and 49% of patients taking oxybutynin reported improvement at 12 weeks. We also reviewed a study comparing immediate-release tolterodine with immediate- 38 release oxybutynin in Chinese women. Two visual analog scales were used; 1 assessed overall severity of symptoms (0 = no symptoms, 10 = maximum severity), and the other assessed change in symptoms from baseline (–5 = maximum improvement, +5 = maximum deterioration). Patients’ perceived improvement in symptoms from baseline was 1 point for oxybutynin and 2 points for tolterodine. These differences were not statistically significant by intention-to-treat analysis (all randomized patients). However, the assessment of change in symptoms was Overactive bladder Page 19 of 73 Final Report Update 4 Drug Effectiveness Review Project statistically significant by a per protocol analysis of patients who completed the study and attended all visits (P=0. In a study of tolterodine 2 mg twice daily compared with oxybutynin 5 mg twice daily, patients were asked if they felt that the study drug had benefited them (yes/no) and if yes, 37 whether it was of little or much benefit. In a per protocol analysis, 45% of tolterodine patients and 46% of oxybutynin patients reported much benefit at 8 weeks. A study comparing trospium 20 mg twice daily to oxybutynin 5 mg twice daily reported subjective appraisal of efficacy by investigators and patients using a 5 category scale: cure, definite improvement, slight improvement, no improvement, and deterioration. After 52 weeks of treatment physicians rated trospium as “cure” in 29% of cases and oxybutynin immediate- 34 release in 17% of cases. Patients were reported as providing “practically identical figures.