By H. Kerth. Yale University.

Paper presented at: Cochrane Collaboration discount 50mg caverta visa, 1997; San Antonio cheap caverta 50mg visa, TX. Methocarbamol in the treatment of cerebral palsy in children. Skeletal Muscle Relaxants Page 31 of 237 Final Report Update 2 Drug Effectiveness Review Project 41. A randomized trial of cyclobenzaprine for the treatment of fibromyalgia. A controlled study of methocarbamol (Robaxin) in acute painful musculoskeletal conditions. Current Therapeutic Research, Clinical & Experimental. A second look at a skeletal muscle relaxant: A double-blind study of metaxalone. Chronic daily headache prophylaxis with tizanidine: a double-blind, placebo-controlled, multicenter outcome study. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. Efficacy of a low-dose regimen of cyclobenzaprine hydrochloride in acute skeletal muscle spasm: results of two placebo-controlled trials. Muscle relaxants for nonspecific low back pain: A systematic review within the framework of the Cochrane Collaboration. Muscle relaxants: chlorzoxazone compared with diazepam (a double- blind study). Lioresal, a new muscle relaxant in the treatment of spasticity--a double-blind quantitative evaluation. A double-blind trial of methocarbamol versus placebo in painful muscle spasm. The plasma endorphin, prostaglandin and catecholamine profile of patients with fibrositis treated with cyclobenzaprine and placebo: a 5-month study. Skeletal Muscle Relaxants Page 32 of 237 Final Report Update 2 Drug Effectiveness Review Project 59. A comprehensive review of clinical trials on the efficacy and safety of drugs for the treatment of low back pain. Treatments for spasticity and pain in multiple sclerosis: a systematic review. Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis. Oral antispastic drugs in nonprogressive neurologic diseases: A systematic review. The treatment of spasticity in multiple sclerosis: a double-blind clinical trial of a new anti-spastic drug tizanidine compared with baclofen. Comparative profile of tizanidine in the management of spasticity. Pharmacological interventions for spasticity following spinal cord injury. Summary of combined clinical analysis of controlled clinical trials with tizanidine. Tizanidine treatment of spasticity: a meta-analysis of controlled, double-blind, comparative studies with baclofen and diazepam. Cyclobenzaprine, diazepam and placebo in the treatment of skeletal muscle spasm of local origin. Tizanidine treatment of spasticity in multiple sclerosis and chronic myelopathy. Tizanidine versus baclofen in the treatment of spasticity in patients with multiple sclerosis. Multi-centre, double-blind trial of a novel antispastic agent, tizanidine, in spasticity associated with multiple sclerosis. Tizanidine versus baclofen in the treatment of spasticity in multiple sclerosis patients. Skeletal Muscle Relaxants Page 33 of 237 Final Report Update 2 Drug Effectiveness Review Project 77.

Standard treatment: The treatment or procedure that is most commonly used to treat a disease or condition purchase 50 mg caverta amex. In clinical trials caverta 100 mg mastercard, new or experimental treatments sometimes are compared to standard treatments to measure whether the new treatment is better. Statistically significant: A result that is unlikely to have happened by chance. Study: A research process in which information is recorded for a group of people. The data are used to answer questions about a health care problem. Study population: The group of people participating in a clinical research study. The study population often includes people with a particular problem or disease. It may also include people who have no known diseases. Subgroup analysis: An analysis in which an intervention is evaluated in a defined subset of the participants in a trial, such as all females or adults older than 65 years. Superiority trial: A trial designed to test whether one intervention is superior to another. Surrogate outcome: Outcome measures that are not of direct practical importance but are believed to reflect outcomes that are important; for example, blood pressure is not directly important to patients but it is often used as an outcome in clinical trials because it is a risk factor for stroke and heart attacks. Surrogate endpoints are often physiological or biochemical markers that can be relatively quickly and easily measured, and that are taken as being predictive of important clinical outcomes. They are often used when observation of clinical outcomes requires long follow-up. Disease-modifying drugs for multiple sclerosis Page 105 of 120 Final Report Update 1 Drug Effectiveness Review Project Survival analysis: Analysis of data that correspond to the time from a well-defined time origin until the occurrence of some particular event or end-point; same as time-to-event analysis. Systematic review: A review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant research and to collect and analyze data from the studies that are included in the review. The extent to which a drug’s adverse effects impact the patient’s ability or willingness to continue taking the drug as prescribed. These adverse effects are often referred to as nuisance side effects, because they are generally considered to not have long-term effects but can seriously impact compliance and adherence to a medication regimen. Treatment regimen: The magnitude of effect of a treatment versus no treatment or placebo; similar to “effect size”. Can be calculated in terms of relative risk (or risk ratio), odds ratio, or risk difference. Two-tailed test (two-sided test): A hypothesis test in which the values that reject the null hypothesis are located in both tails of the probability distribution. For example, testing whether one treatment is different than another (rather than testing whether one treatment is either better than another). Type I error: A conclusion that there is evidence that a treatment works, when it actually does not work (false-positive). Type II error: A conclusion that there is no evidence that a treatment works, when it actually does work (false-negative). Validity: The degree to which a result (of a measurement or study) is likely to be true and free of bias (systematic errors). Variable: A measurable attribute that varies over time or between individuals. Variables can be • Discrete: taking values from a finite set of possible values (e. Washout period: [In a cross-over trial] The stage after the first treatment is withdrawn, but before the second treatment is started. The washout period aims to allow time for any active effects of the first treatment to wear off before the new one gets started. Disease-modifying drugs for multiple sclerosis Page 106 of 120 Final Report Update 1 Drug Effectiveness Review Project Appendix B. Black Box warnings for included drugs Drug names Active ingredients Boxed warnings WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability.

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In the second- summarize recent updates on the use of monoclonal antibodies generic 100 mg caverta visa, line setting buy 50mg caverta mastercard, a sequential therapy of brentuximab vedotin fol- small-molecule signal transduction inhibitors, epigenetic modula- lowed by ICE (ifosfamide, carboplatin, etoposide) chemotherapy tors, and agents that modulate the microenvironment. Monoclonal antibodies Although brentuximab vedotin has significant activity in HL, other Therapeutic antibodies targeting cell surface receptors have contrib- strategies to target CD30 have been disappointing. Most recently, a uted to standard-of-care treatments for multiple solid and hemato- novel tetravalent bispecific antibody against CD30 and CD16 logic malignancies. In HL, targeting cell surface receptors within (AFM13), which recruits natural killer cells and macrophages to the TNF and BCR pathways has demonstrated efficacy. CD30 regions to illicit an immune response, was evaluated. After several failed attempts to develop naked The rationale for targeting CD20 in patients with classical HL is anti-CD30 antibody therapy, remarkable progress was achieved by to target HRS cells, which sometimes express CD20, but also to conjugating the naked antibody SGN30 to antitubulin monomethyl eliminate CD20-expressing reactive B cells in the microenviron- auristatin E to generate the antibody drug-conjugate brentuximab ment, which can provide survival signals to HRS cells. In a pivotal phase 2 clinical trial in patients who were phase 2 trials of rituximab plus ABVD (R-ABVD) were reported previously treated with autologous stem cell transplantation, bren- recently. In the first study, R-ABVD therapy resulted in a 5-year tuximab vedotin showed an overall response rate (ORR) of 75%, event-free survival rate of 83%5; in the second, it resulted in a 394 American Society of Hematology Figure 1. In a phase 1a clinical trial, comparing rituximab-ABVD with standard ABVD in patients lucatumumab administered every 4 weeks showed a 10% partial with high-risk, advanced-stage cHL. In a subsequent phase 2 trial, 3 of 18 (17%) of brentuximab vedotin, it remains unclear where CD20-targeted patients with relapsed HL achieved PRs. Selected PI3K inhibitors in clinical trials PI3K inhibitor Administration Target Clinical trial no. CAL-101 Oral p110 subunit PI3K NCT01393106 IPI-145 Oral PI3K and PI3K NCT01476657 BAY80–6946 IV Pan-class I PI3K NCT01660451 (NHL) TGR-1202 Oral PI3K NCT01767766 (CLL, NHL, PTCL) BKM-120 Oral Pan-PI3K NCT01719250 (NHL) CUDC-907 Oral PI3K and HDAC NCT01742988 (lymphoma, MM) AMG-319 Oral PI3K NCT01300026 CLLindicateschroniclymphocyticleukemia;NHL,non-HL;PTCL,peripheralT-celllymphoma;andMM,multiplemyeloma. PD1/PD-L1 IPI-145 may have clinical activity in patients with relapsed HL. Other HRS cells aberrantly express PD-L1, which is typically expressed PI3K inhibitors are also being evaluated in this disease (Table 1). PDL-1 interacts with the PD-1 receptor on T cells to dampen the immune response by inhibiting TCR signaling. In a phase 2 study, the mTOR inhibitor everolimus produced clinical activity. CT-011 is a humanized anti-PD-1 monoclonal an ORR of 47% in 19 patients (Table 2). Class-related side effects were observed Nivolumab (BMS-936558) is a monoclonal anti-PD-1 antibody and included stomatitis, thrombocytopenia, fatigue, and grade 1/2 actively being studied in a phase 1 trial for hematologic malignan- pneumonitis in 6 patients. The results of this trial are prompt additional evaluation of rapalogs in combination with highly anticipated. The dose-limiting toxicity was thrombocy- Constitutive activation of the JAK/STAT, NF- B, PI3K, and 12 topenia. Early results from the phase 1 portion of the study MEK/ERK pathways protect HRS cells from apoptotic signals. As a result, targeting these nodal results compare favorably with the single-agent activity of each pathways by small-molecule inhibitors has a dual effect on the HRS drug (Figure 2). JAK/STAT PI3K/AKT/mTOR The JAK/STAT signaling pathway is frequently activated in HRS PI3K is a ubiquitously expressed phosphokinase that transduces cells. Activation mutations of JAK2 are rare in patients with extracellular signals from cell surface receptors such as CD40, lymphoma. In HL, the JAK/STAT pathway is activated as a result of chemokine receptors, and BCR (Figure 1). There are 4 isoforms of genomic amplification of JAK2 and/or inactivating mutations in an inhibitor of JAK activity, SOCS1. Activation of PI3K results in activation of downstream kinases, including AKT and mammalian target of therapeutic potential of JAK inhibitors in HL was shown by a phase rapamycin (mTOR), which regulate several key cellular functions 1 study of the JAK inhibitor SB1518, a selective inhibitor of JAK2 including survival, metabolism, and immunity. In that study, 14 of 34 total lymphoma patients had cHL. AZD1480, a promising clinical activity in a variety of B-cell malignancies. In concentrations by down-regulating the expression of Th2 cytokines a different strategy, a dual inhibitor of PI3K and PI3K and PI3K and chemokines (IL-13 and TARC), as well as STAT3-mediated was developed to produce the small-molecule inhibitor IPI-145. Response rates achieved with single agents in patients with relapsed HL Agent Target Administration N ORR CR Reference Brentuximab CD30 IV 102 75% 34% Younes et al1 Everolimus mTOR PO 19 47% 5% Johnston et al14 Vorinostat Class I/II HDAC PO 25 4% 0% Kirschbaum et al29 Mocetinostat HDAC 1, 2, weak HDAC 3, 11 PO 51 27% 4% Younes et al32 Panobinostat Class I/II/IV HDAC PO 129 27% 4% Younes et al33 Entinostat HDAC 1, 3 PO 49 16% 0% Younes et al35 396 American Society of Hematology HDAC inhibitors with activity against class I and II HDACs.

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Due to various methodological limitations discount 50 mg caverta free shipping, these studies do not provide good evidence for long-term effectiveness order caverta 100mg line, even for methylphenidate. In a cross-sectional follow-up study of young men diagnosed with “persistent hyperactivity” at ages 6 to 12 years, those who had not received medication were compared with 167 a group that had received methylphenidate for at least 3 years during childhood. The groups were initially seen in different time-periods, separated by 5 to 15 years. Because the groups were from different periods, a third group of normal children who were contemporaneous to the methylphenidate group was added. The sizes of the groups also differed, with 64 in the non- treated hyperactive group, 20 in the methylphenidate treated group, and 20 in the normal Attention deficit hyperactivity disorder 64 of 200 Final Update 4 Report Drug Effectiveness Review Project controls, and data were not available for all subjects on all questions. Mean follow-up of the hyperactive groups was 10 to 12 years. No information on baseline characteristics from childhood was given. No consistent differences in functional outcomes were found between the methylphenidate and untreated groups (Table 10). Considering the potential confounding of differences in the years the children were treated, and the very small numbers of subjects per group per variable, these results should be interpreted with caution. Long-term functional outcomes of methylphenidate from Hechtman, 167 1984 MPH Variable Favors group Nontreated P value Age at follow-up NA 22 years 20 years <0. The methylphenidate group in this study was previously reported after 5 years of follow- up (as adolescents), with comparison groups of boys treated with chlorpromazine or untreated 165 boys. This study reported academic performance, with no differences found between the groups. Adolescents (ages 13 to 17) Evidence on the effectiveness of pharmacotherapy for ADHD in adolescents was very limited (Evidence Tables 1 and 2). We did not find any effectiveness trials or long-term observational studies (assessing functional or safety outcomes) in adolescents with ADHD. Adolescents were studied in 1 head-to-head trial of immediate-release methylphenidate and methylphenidate SR 169 170-179 (OROS) and in 9 placebo-controlled trials of methylphenidate. Mixed-age populations including adolescents were studied in efficacy trials of atomoxetine, however data were not stratified by school age and adolescents so are considered in the school-age children section (above). Direct comparisons ® Immediate-release methylphenidate compared with methylphenidate OROS (Concerta ). A single, very small, single blinded crossover study of 6 adolescent boys showed methylphenidate OROS superior to immediate-release methylphenidate on some simulated measures of driving Attention deficit hyperactivity disorder 65 of 200 Final Update 4 Report Drug Effectiveness Review Project 169 skills, dependent on the time of day of testing. ADHD was confirmed using the DePaul ADHD Rating Scale IV (parents completed), the Diagnostic Interview Schedule for Children (DISC-IV), and the Standardized Interview for Adult ADHD. After 7 days of dosing, the teens performed significantly better while taking methylphenidate OROS on 3 of 9 measures (inappropriate braking, missed stop signals, and speed control) at each testing time (2 PM, 5 PM, 8 PM, and 11 PM). Because only F- and P values were reported, it is not possible to interpret the magnitude of differences found. An analysis of a combined score of 7 (of 9) measures at each of the 4 time points indicated that there were no differences between the formulations at the 2 PM and 5 PM test times, but the scores were significantly lower with the immediate-release formulation at the 8 PM and 11 PM times (P<0. Self-evaluations of risky driving behavior did not show any differences between the formulations. Since 2 teens were previously on methylphenidate OROS, 2 had been taking immediate-release methylphenidate, and the only person blinded was an observer in the driving simulator, it would be important to know the effect of prior medication and order of randomization. Methylphenidate OROS compared with mixed amphetamine salts XR. A 17-day, small (N=35) crossover study compared the effect of stimulant use on the driving ability of adolescents with 180 ADHD. There was no significant difference between methylphenidate OROS 72 mg once daily and mixed amphetamine salts XR 30 mg once daily in self-reported symptom improvement among participants (P=0. However, subjective ratings of driving performance by participants failed to detect a difference between the 2 study drugs. A 4-week, placebo-controlled study of extended-release mixed ® amphetamine salts (Adderall XR ) using a forced-dose titration schedule (up to 40 mg once daily) assessed efficacy in 287 patients using the ADHD rating scale IV and Clinical Global Impression-Improvement Scale scores. All doses of extended-release mixed amphetamine salts were associated with significant improvement in ADHD rating scale IV scores compared with placebo.

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No significant differences in LSAS total score were observed between any escitalopram treatment group and the paroxetine group in the intention-to-treat analysis purchase caverta 50mg mastercard. The authors did not report any intention-to-treat results for secondary outcome measures caverta 100mg line. In the observed-cases-analysis at 24 weeks, escitalopram 20 mg/d was superior to paroxetine 20 mg/d on the CGI-S. Significant differences (favoring escitalopram 20 mg/d) were noted on the SDS at weeks 16 and 20, but differences between escitalopram and paroxetine were not significantly different at week 24. Indirect comparisons of escitalopram, fluvoxamine, paroxetine, and sertraline A good meta-analysis of second-generation antidepressants for social anxiety disorder utilized data of more than 6500 patients from three head-to-head trials and 15 placebo-controlled trials. To determine the comparative efficacy among drugs, authors employed network meta- 212 analyses. With the exception of one study, which included children and adolescents, trial populations consisted of adults with mean ages from 35 to 41 years and a relatively equal distribution of males and females. Baseline disease severity varied among participants (range of LSAS scores 74-97). Trials included in the analysis had to have a minimum duration of 12 weeks (range of study duration 12-28 weeks). Individual drugs were included in the network meta- Second-generation antidepressants 66 of 190 Final Update 5 Report Drug Effectiveness Review Project analysis when at least two similarly designed trials provided CGI-I data. Authors conducted a network-meta-analysis and found no significant differences in response among included SSRIs. Because of the limited number of component studies, however, estimates of relative effects were imprecise with wide confidence intervals which encompassed potentially important differences. SNRIs compared to SSRIs in adult outpatients with social anxiety disorder A good meta-analysis conducted indirect comparisons of second-generation antidepressants for the treatment of social anxiety disorder. Two fair double-blinded RCTs compared the efficacy and tolerability of one second-generation antidepressant to an SSRI. An additional Indirect comparisons of venlafaxine with SSRIs The above mentioned good meta-analysis of second-generation antidepressants for social anxiety disorder conducted indirect comparisons of venlafaxine with various SSRIs (escitalopram, fluvoxamine, paroxetine, and sertraline) using network-meta-analysis of data on more than 6500 212 patients three head-to-head trials and 15 placebo-controlled trials. The authors found no significant differences in any of the possible comparisons between venlafaxine and escitalopram, fluvoxamine, paroxetine, or sertraline. However, estimates had wide confidence intervals and encompassed potentially important differences. Venlafaxine compared with paroxetine 208, 210 Two 12-week multicenter trials compared venlafaxine ER to paroxetine and placebo. A 208 European trial randomized 436 patients with social anxiety disorder and an American trial 210 randomized 440 patients with social anxiety disorder to venlafaxine ER (75-225 mg/d), paroxetine (20-50 mg/d), or placebo. Eligible patients were 18 years or older who met DSM-IV criteria for social anxiety disorder at least 6 months before enrollment. In the European trial, significantly more females were randomized to placebo than to venlafaxine or paroxetine. The primary outcome measure was the LSAS; secondary outcome measures included the CGI-I, CGI-S, SPI, and SDI. The European trial also included a measure of work productivity WPAI. At 12 weeks, no significant differences in any outcome measure were observed between venlafaxine ER and paroxetine in either trial. Both venlafaxine ER and paroxetine were significantly better than placebo for all primary and secondary outcome measures (P<0. SSRIs compared to placebo in adult outpatients with social anxiety disorder One meta-analysis, one systematic review, and five placebo-controlled trials provide additional evidence. SSRIs compared with placebo One systematic review evaluated the efficacy of SSRIs compared with placebo in the treatment 213 of social anxiety disorder in adults. This review included placebo-controlled trials of SSRIs ranging in duration from 10-24 weeks and converted treatment effects to standardized effect sizes. Authors concluded that, in general, SSRIs are more effective than placebo in treating social anxiety disorder. Second-generation antidepressants 67 of 190 Final Update 5 Report Drug Effectiveness Review Project Escitalopram compared with placebo 215 One fair 12-week study compared flexible doses of escitalopram to placebo.

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