By O. Charles. Canisius College. 2019.
Antithymocyte remission acute myeloid leukemia in young and middle-aged globulin for graft-versus-host disease prophylaxis in transplants adults: beneﬁts for whom? Graft-versus- tion purchase nizagara 100 mg fast delivery erectile dysfunction causes in young males, and late transplant-related mortality: long-term follow-up leukemia reactions after bone marrow transplantation buy nizagara 50 mg free shipping erectile dysfunction adderall. Risk factors for unrelated hematopoietic cell transplantation for acute myelog- lymphoproliferative disorders after allogeneic hematopoietic enous leukemia purchase 25mg nizagara mastercard erectile dysfunction medicine. Fludarabine- for natural killer cell receptor genes leads to superior survival melphalan conditioning for AML and MDS: alemtuzumab after unrelated transplantation for acute myelogenous leukemia. Microchimerism and allogeneic anti-tumor reactions after allogeneic hematopoietic cell trans- transplantation: We need the proof in the pudding. Immunogenetic consequences of vascular anastomo- expanded T regulatory cells in adults transplanted with umbili- ses between bovine twins. Claas FH, Gijbels Y, van der Velden-de Munck, van Rood 2011;117(3):1061-1070. Induction of B cell unresponsiveness to noninherited 26. The role of HLA maternal HLA antigens during fetal life. Effect of HLA- necessary not only for blood type but also for HLA? Bone matching recipients to donor noninherited maternal antigens on Marrow Transplant. High-resolution donor- tion for hematologic malignancy. Biol Blood Marrow Trans- recipient HLA matching contributes to the success of unrelated plant. HLA-C antigen plant outcome in hematological malignancies. Proc Natl Acad mismatch is associated with worse outcome in unrelated donor SciUSA. Indirect evidence that associate with adverse outcomes in hematopoietic stem cell maternal microchimerism in cord blood mediates a graft-versus- transplantation. Scaradavou A, Carrier C, Mollen N, Stevens C, Rubinstein P. Detection of maternal DNA in placental/umbilical cord blood Lancet Oncol. Effect of donor-recipient presence of maternal cells in human umbilical cord blood. Exp HLA matching at HLA A, B, C, and DRB1 on outcomes after Hematol. Survival after T dysplastic syndrome: a retrospective analysis. NK cells–from bench to haematopoietic cell transplantation from matched unrelated clinic. Donors with GvHD prophylaxis with or without anti-T-cell globulin ATG- group B KIR haplotypes improve relapse-free survival after fresenius. Young1 1Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD Historically viewed in isolation as an odd, rare, and invariably fatal blood disease, aplastic anemia is now of substantial interest for its immune pathophysiology, its relationship to constitutional BM failure syndromes and leukemia, and the success of both stem cell transplantation and immunosuppressive therapies in dramatically improving survival of patients. Once relegated to a few presentations in the red cell and anemia sessions of the ASH, the Society now sponsors multiple simultaneous sessions and plenary and scientiﬁc committee presentations on these topics. This update emphasizes developments in our understanding of immune mechanisms and hematopoietic stem cell biology and new clinical approaches to stem cell stimulation as a therapy, alone and in combination with conventional suppression of the aberrant immune system. Introduction There are abundant laboratory data supporting an immune Advances in BM failure syndromes now are almost annual topics in pathophysiology, but detailed mechanisms are lacking—as they the ASH Educational Program, and this review therefore empha- are for most human autoimmune or immune-mediated diseases. The reader is referred to more comprehen- lymphocytes and type 1 cytokines appear to be the proximate sive publications for fuller discussions and ample bibliographies. T-regulatory cells appeared to be deﬁcient in quantity10 and function11 and their numbers were strikingly different in the Blood counts can be decreased in overwhelming infection (eg, bacterial sepsis) and secondary to a few diseases (eg, cirrhosis with randomized trial of horse versus rabbit ATG, with recovery hypersplenism, systemic lupus), but severe persistent pancytopenia correlating with better response. In large granular lymphocyto- has a limited differential diagnosis and almost always implies BM sis, in which a single T-cell clone dominates and suppresses BM involvement. The “empty” BM deﬁnes aplastic anemia by a simple function, acquired mutations in STAT3 are prevalent and function- ally would result in constitutive activation12 (acquired STAT3 and uniform criterion with little pathologic variation or need for reﬁned classiﬁcation based on morphology. The BM is not truly mutations have been reported in autoimmune diseases). These 4 mutations may also be present in acquired aplastic anemia. Mouse models of aplastic anemia, produced by the destruction of BM cells using radiation, Genomics applied to oligoclones in BM failure states might cytotoxic drugs, and immune cells, have been useful in deﬁning the reveal an acquired genetic basis for abnormal persistence of an hematopoietic stem cell and illustrating the potency of small initially appropriate immune response (Figure 1). Long-term initiating cells and cobble- stone-forming cells are as close as we can assay the human stem cells and these too are sparse in all patients. Despite sophisticated Immune-mediated BM destruction assays, blood counts, presumably reﬂecting stem cell reserve, are The most powerful evidence that acquired aplastic anemia in adults the best predictors of outcome in nontransplantation therapy. In our Although the “Camitta criteria” continue to be used to deﬁne severe most recent National Institutes of Health (NIH) clinical trial of aplastic anemia, in the era of immunosuppression, reticulocytes and standard horse antithymocyte globulin (ATG) and cyclosporine, lymphocytes pretreatment14 and the robustness of the hematologic nearly 70% of patients had hematologic responses at 6 months. Likely also correlating with stem cell reserve ATG or Campath, a further 30% of primary nonresponders show are the better outcomes in children compared with adults and, as hematologic improvement to transfusion independence. That a one-third, either relapse or need sustained cyclosporine administra- stem cell stimulator small molecule can improve blood counts in tion to maintain their blood counts. A long taper of cyclosporine can some chronic refractory aplastic anemia patients and accelerate delay relapse and patients may do well on very low doses of drug. Somatic mutations in lymphocytes might drive an aberrant immune response. Tissue damage is a normal component of an inﬂammatory response and resolves with withdrawal of the stimulating antigen. Acquired mutations, altering proliferation, susceptibility to apoptosis, or a variety of signaling pathways in an effector population or in regulatory cells would lead to persistence of a clone, tissue destruction, exposure of new antigens, and further recruitment of immune cells. Is the stroma responsible for require clariﬁcation for the practicing hematologist given the failure to respond to immunosuppression? This hypothesis seems novelty of the telomere diseases, the availability of clinical assays, unlikely because engraftment rarely hinders stem cell transplanta- and easy confusion between genetic, physiologic, and pathophysi- tion in this population and there is an absence of supportive ologic telomere attrition. The simpler and more likely chromosomes consisting of hundreds of hexamer repeats (TTAGGG) reason for lack of response to immunosuppression is the limited and associated shelterin proteins. The telomere structure protects the number of hematopoietic stem cells that are also functionally unable end of the chromosome from recognition by DNA excision enzymes to regenerate the failed hematopoietic compartment appropriately. Nevertheless, due to the asymmetry of DNA replication, loss of telomeric DNA is inevitable with every Genetics of BM failure in “acquired” aplastic anemia cell division, and telomere length is the explanation for the Hayﬂick The historically clear distinction between constitutional and ac- phenomenon (limited cell division in tissue culture) and a “mitotic quired aplastic anemia is now blurred due to the discovery of clock” of an individual cell. Indeed, telomeres shorten physiologi- mutations in the telomere repair complex in otherwise typical adult cally with aging of an organism, including humans.
For English native speakers purchase nizagara 25mg overnight delivery impotence psychological treatment, words such as Sicherungsverwahrung 25mg nizagara otc erectile dysfunction 60 year old man, Grundsatzurteil and Bundesgerichtshof are new order nizagara 100 mg mastercard erectile dysfunction drugs nz, whereas evolución, democracia and economia are not. At 600 new words per month, progress is evident week after week. Rapid word accumulation is paramount for two reasons. First, you need to recognise the words that your auditory brain cortex will soon be able to ‘cut out’ from spoken language (see Chapter 2, Listening). Second, word nailing accelerates your transition from an illiterate to a literate person and brings you closer to the most pressing short-term objective: reading! As soon as possible, you must move into territory where you are able to read everything... At first, the process is slow, like deciphering hieroglyphics, but if you persist, your reading abilities will soon speed up. Intense reading will trigger quantum leaps in understanding. In one hour, reading exposes you to as much as 20,000 words. Just to make sure that we understand each other: I don’t find word nailing thrilling and I can immediately name dozens of activities I would prefer to do. Remember Chapter 1: The number of words you are familiar with determines your language abilities. Nailing can be divided into three distinct activities: learning words, repeating words, and controlling words. Beginners need two-column lists that put new and native words face to face. Check the spelling, imagine the sound of the word and make a guess at the resistance a word is likely to oppose: easy to learn or not? Four- syllable words such as perseverance will demand more time than monosyllabics such as and, or, and but. Go through the list a second and third time, either line by line or leaping at random from word to word. Push the words around in your mind, squeeze them, press them, and stretch them. Finally, test yourself by covering first the right column and then the left column. As thrilling as 100 percent results are, the first learning session is only the starting point for a weeklong consolidation process. Remember the forgetting curve of the Memory chapter. After one day, the percentage of correct answers is dramatically down, and after one month, recall may be 20 percent or less. As learning is nothing and recalling is everything, the second pillar of word nailing is repetition. Find out which strategy fits you best, either daily repetitions or repetitions on day 1, 3, 6, 10, 17, and 31, or any other regime. You will soon notice that after every re- exposure, memory traces are easier to reactivate. Determine that every single word has safely arrived in lifelong memory. Very young children ask their family for help, and a grandmother might interrogate her grandson, ‘Young boy, please tell me what açúcar means. Revisiting the word lists frequently and marking ‘difficult’ words for further revision is one such system. Alternatively, you can use index cards or word trainers on electrical devices. At a rate of 20, 30, or 40 new words a day, the time will come when you will feel like a force-fed French goose. The prevention: nail words five days a week and stop nailing at weekends. If saturation develops nonetheless, pause for an entire week. Good language manuals usually present around 2,000 words – that is far short of your final word score of 5–15,000. This is a miserable situation, because you are too good to continue working with manuals, but not good enough for reading essays, newspapers or novels. At this early stage, not even dictionaries are helpful – deciphering a text where half of the words are unknown is achingly slow. There is one acceptable solution: nailing carefully selected word compilations that are grouped by topic and divided into basic and advanced vocabulary. Good compilations present around 7,000 words and offer free pronunciation audio files (see www. Define the number of pages you will nail every day and start ploughing your way through them. People who have never used these books sometimes observe that learning hundreds of pages of words out of context is not an exciting perspective. I agree, but the alternative – looking up 10,000 words in a dictionary – is not sexier. Anticipate at least two rounds and possibly another round after 6 to 12 months. To your satisfaction, you will realise that daily listening to your audio sources (remember the manual CDs, TV programmes and audio books of the Listening chapter) has paved the way to understanding grammar. In fact, humans have an innate ability to grasp grammar, and this ability doesn’t disappear with adult age. Don’t be afraid of the technical terms of grammar, the nouns, pronouns, adverbs, tenses, modes, etc. Think of the parts that you know from your car – gearbox, headlights, battery, brakes, suspension, chassis, radiator, dipstick, cylinder, driveshaft, exhaust pipe, jack, lug nuts, spark plug, hubcap, etc. In comparison, becoming familiar with a handful of grammar terms is a bagatelle. Working through compilations of frequent words is like working on an assembly line. To break the boring rhythm, try and read real-world texts from time to time. As your word repertoire increases and the number of missing words diminishes, you will one day discover how exciting it is to work on essays, newspapers or novels. Underline new words, search for them in the dictionary, and write them down in a notebook. At this point, you can even slow down your nailing rhythm, but only on one condition: that you extract from your reading sources double the number of words that is on your nailing schedule.
Importance of baseline prognostic factors with increasing time since initiation of highly active antiretroviral therapy: collaborative analysis of cohorts of HIV-1-infected patients generic 100mg nizagara visa impotent rage man. Variable impact on mortality of AIDS-defining events diagnosed during com- bination antiretroviral therapy: not all AIDS-defining conditions are created equal nizagara 100mg low cost erectile dysfunction operations. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis buy generic nizagara 25mg online erectile dysfunction song. Late presenters in an HIV surveillance system in Italy during the period 1992- 2006. Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries. Missed opportunities for earlier HIV diagnosis within primary and sec- ondary healthcare settings in the UK. Carnicer-Pont D, de Olalla PG, Cayl JA; AIDS Working Group. HIV infection late detection in AIDS patients of an European city with increased immigration since mid 1990s. Prevention of HIV-1 Infection with Early Antiretroviral Therapy. Factors associated with short-term changes in HIV viral load and CD4(+) cell count in antiretroviral- naive individuals. Cozzi-Lepri A, Phillips AN, d’Arminio Monforte A, et al. When to start HAART in chronically HIV-infected patients: evidence from the ICONA study. Duffus WA, Youmans E, Stephens T, Gibson JJ, Albrecht H, Potter RH. Missed opportunities for early HIV diag- nosis in correctional facilities. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Major clinical outcomes in antiretroviral therapy (ART)-naive partici- pants and in those not receiving ART at baseline in the SMART study. Intermittent viraemia and immune reconstitution in patients with more than 10-15 years of antiretroviral therapy: baseline values still matter. Long-Term CD4+ T-Cell Response to Highly Active Antiretroviral Therapy According to Baseline CD4+ T-Cell Count. The frequency and clinical implications of a discordant CD4 count and CD4 percentage. Perturbation of CD4+ and CD8+ T-cell repertoires during progres- sion to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Immunologic and clinical responses to highly active antiretroviral therapy over 50 years of age. CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater. When to start ART 175 Grinsztejn B, Hosseinipour MC, Ribaudo HJ, et al. Effects of early versus delayed initiation of antiretroviral treat- ment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Timing of antiretroviral therapy for HIV-1 infection and tuber- culosis. CD4 lymphocyte percentage predicts disease progression in HIV-infected patients initiating HAART with CD4 lymphocyte counts >350 lymphocytes/mm3. Jenness SM, Murrill CS, Liu KL, Wendel T, Begier E, Hagan H. Missed opportunities for HIV testing among high- risk heterosexuals. Evidence supporting initiation of therapy at CD4+ lymphocyte counts <350 cells/uL. Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/uL in HIV type 1-infected individuals receiving potent antiretroviral therapy. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Effect of early versus deferred antiretroviral therapy for HIV on sur- vival. The high cost of medical care for patients who present late (CD4 <200 cells/microL) with HIV infection. Immune reconstitution is comparable in antiretroviral-naive subjects after 1 year of successful therapy with a nucleoside reverse-transcriptase inhibitor- or protease inhibitor-containing antiretroviral regimen. CD4+ T-lymphocyte nadir and the effect of highly active antiretroviral therapy on phenotypic and functional immune restoration in HIV-1 infection. Frequency, determinants and consequences of delayed access to care for HIV infection in France. Optimum time to start antiretroviral therapy during HIV-associated opportunistic infections. Cellular restoration in HIV infected persons treated with abacavir and a protease inhibitor: age inversely predicts naive CD4 cell count increase. Early, uninterrupted ART is associated with improved outcomes and fewer toxicities in the HIV Outpatient Study (HOPS). National review of deaths among HIV-infected adults. Natural history of HIV type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men. Early versus delayed initiation of antiretroviral therapy for con- current HIV infection and cryptococcal meningitis in sub-saharan Africa. Manzardo C, Zaccarelli M, Agüero F, Antinori A, Miró JM. Optimal timing and best antiretroviral regimen in treat- ment-naive HIV-infected individuals with advanced disease. Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: col- laborative analysis of prospective studies. HIV treatment response and prognosis in Europe and North America in the first decade of highly active antiretroviral therapy: a collaborative analysis. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV- 1 infection. Risk factors and outcomes for late presentation for HIV-positive persons in Europe: results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE). Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase. Patients presenting with AIDS in the HAART era: a collaborative cohort analysis. Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+ cell strata.
Tolerance and Dependence Risk with the Use of Carisoprodol buy nizagara 50 mg on-line erectile dysfunction pills cvs. A near-fatal overdose of carisoprodol (SOMA): A case report effective 100 mg nizagara impotence vs erectile dysfunction. A review of carisoprodol deaths in Jefferson County order nizagara 100 mg line erectile dysfunction injection test, Alabama. Possible dangerous interaction of oxycontin and carisoprodol. Use of carisoprodol by substance abusers to modify the effects of illicit drugs. Sensitive GC-MS quantitation after solid phase extraction in 19 fatal cases. Cyclobenzaprine (Flexeril(TM)): Report of a postmarketing surveillance program. Skeletal Muscle Relaxants Page 40 of 237 Final Report Update 2 Drug Effectiveness Review Project Table 1. O verview ofincluded system aticreviews onskeletalm uscle relaxants A uth or Skeletalm uscle N um berofincluded Y ear Purpose ofstudy relaxants evaluated studies and patients Q uality M ainfindings System aticreviews M ontane A ssess th e efficacy of Tiz anidine 10 placebo-controlled trials G ood. A ctive treatmentgenerally neurologicdiseases betterth anplacebo butoutcomes h eterogeneous (excludes multiple 2 h ead-to-h ead trials (1 and functionaloutcomes seldom analyz ed. O verview ofincluded system aticreviews onskeletalm uscle relaxants A uth or Skeletalm uscle N um berofincluded Y ear Purpose ofstudy relaxants evaluated studies and patients Q uality M ainfindings System aticreviews Sh akespeare A ssess th e comparative Tiz anidine 26 placebo-controlled trials G ood. O verallquality ofstudies fair,with average quality 62 safety ofcyclobenz aprine cyclobenz aprine score 4. N o cleardifferences forsleepmeasures, painrelief,fatigue,and tenderpoints. Skeletal Muscle Relaxants Page 42 of 237 Final Report Update 2 Drug Effectiveness Review Project Table 1. O verview ofincluded system aticreviews onskeletalm uscle relaxants A uth or Skeletalm uscle N um berofincluded Y ear Purpose ofstudy relaxants evaluated studies and patients Q uality M ainfindings System aticreviews Beard A ssess th e efficacy of Tiz anidine 19 placebo controlled trials G ood. O verallquality ofstudies poor,with wide variety of 61 differentdrugtreatments Baclofen (9 baclofen,5 dantrolene,5 outcome measures used. O verview ofincluded system aticreviews onskeletalm uscle relaxants A uth or Skeletalm uscle N um berofincluded Y ear Purpose ofstudy relaxants evaluated studies and patients Q uality M ainfindings System aticreviews vanTulder A ssess th e effectiveness Tiz anidine 30 trials (3 cyclobenz aprine G ood. O rph enadrine ch lorz oxaz one,1 dantrolene Diaz epam* vs. System aticreviews Taricco A ssess th e effectiveness Tiz anidine 9 trials (2 baclofenvs. Tiz anidine more effective th anplacebo forA sh worth injury patients score butnotforfunctionalstatus. N o difference 218 patients overall betweenbaclofenand placebo. Skeletal Muscle Relaxants Page 44 of 237 Final Report Update 2 Drug Effectiveness Review Project Table 1. O verview ofincluded system aticreviews onskeletalm uscle relaxants A uth or Skeletalm uscle N um berofincluded Y ear Purpose ofstudy relaxants evaluated studies and patients Q uality M ainfindings System aticreviews L ataste A ssess th e comparative Tiz anidine 20 trials (14 vs. M eth ods of U nable to assess quality ofincluded studies. Tiz anidine sligh tly ofincluded bettertolerated th andiaz epam and baclofen. W ith drawals due to adverse events 4% ontiz anidine vs. M eta-analyses G roves A ssess th e efficacy and Tiz anidine 10 trials (7 vs. Insufficient N o significantdifferences betweentiz anidine and 69 tolerability oftiz anidine Baclofen vs. W allace A ssess th e efficacy and Tiz anidine 3 placebo-controlled trials F air. Insufficient See results forG roves 1998 forresults ofh ead-to- 68 tolerability oftiz anidine Baclofen with 525 patients detailofincluded h ead studies. F requentadverse events on diaz epam)with 270 patients appropriately tiz anidine were dry mouth (49% ),somnolence (48% ),asth enia (41% ),diz z iness (16% ),h eadach e (12% ). Skeletal Muscle Relaxants Page 45 of 237 Final Report Update 2 Drug Effectiveness Review Project Table 1. O verview ofincluded system aticreviews onskeletalm uscle relaxants A uth or Skeletalm uscle N um berofincluded Y ear Purpose ofstudy relaxants evaluated studies and patients Q uality M ainfindings System aticreviews N ibbelink A ssess th e efficacy of C yclobenz aprine 20 randomiz ed trials F air. Skeletal Muscle Relaxants Page 46 of 237 Final Report Update 2 Drug Effectiveness Review Project Table 2. Overview of head-to-head trials of skeletal muscle relaxants for spasticity Study Population Interventions Year Number Withdrawals Dose Quality enrolled Main outcomes assessed Main results (overall) Tizanidine versus baclofen Tizanidine mean Bass Multiple Spasticity: 6 point scale No significant 10% (5/52) 17 mg/day 72 sclerosis Strength: 6 point scale differences 1988 Functional status: Kurtzke between 27% (13/48) Baclofen mean FAIR 66 functional scale interventions for 35 mg/day Disability: Pedersen functional main outcomes disability scale Preference: patient assessment Tizanidine mean Corston Lower limb Spasticity: 3 point scale No significant None reported 22 mg/day 50 spasticity due to Strength: 5 point scale differences 1981 various causes General mobility: 3 point scale between Baclofen mean FAIR Urinary frequency: 3 point scale interventions for 40 mg/day 10 Gait: 3 point scale main outcomes Tizanidine Eyssette Multiple Spasticity: 5 point scale No significant 16% (8/50) titrated to 24 73 sclerosis Stretch reflex: 1-5 scale differences 1988 mg/day Functional status: Unspecified between 12% (6/50) FAIR 100 methods interventions Baclofen titrated Efficacy and tolerability: to 60 mg/day Unspecified methods Tizanidine 12-24 Hoogstraten Multiple Spasticity: Ashworth scale and No significant 6% (1/16) mg/day 74 sclerosis patient self-report (5 point scale) differences 1988 Disability: Kurtzke Expanded between 25% (4/16) Baclofen 15-60 FAIR 16 Disability Status Scale interventions mg/day Functional status: Kurtzke (Ashworth scale Functional Systems scores not Incapacity status: Minimal record of reported) disability for multiple sclerosis Ambulation: Ambulation index Clonus and reflexes: Unspecified methods Muscle strength and pain: 5 point scales Efficacy and tolerance: -3 to +3 scales Tizanidine mean Medici Spasticity due Spasticity: Ashworth scale and No significant 7% (1/15) 20 mg/day 75 to various patient self-report (4 point scale) differences 1989 causes Muscle strength: 5 point scale between 27% (4/15) Baclofen mean FAIR Clonus: 3 point scale interventions 50 mg/day 30 Functional status: Kurtzke (Ashworth scale Expanded Disability Status Scale scores not Global assessments: Unspecified reported) methods Skeletal Muscle Relaxants Page 47 of 237 Final Report Update 2 Drug Effectiveness Review Project Table 2. Overview of head-to-head trials of skeletal muscle relaxants for spasticity Tizanidine Newman Multiple Spasticity: Ashworth scale No significant 11% (4/36) titrated to 16 76 sclerosis (32) or Functional status: Kurtzke and differences 1982 mg/day syringomyelia Pedersen scales between 17% (6/36) FAIR (4) interventions Baclofen titrated (Ashworth scale to 40 mg/day 36 scores not reported) Tizanidine mean Rinne Multiple Spasticity: Ashworth scale No significant 6% (1/16) 11 mg/day 71 sclerosis (24) or differences 1980 (2) cervical between 6% (1/16) Baclofen mean FAIR myelopathy (8) interventions 51 mg/day (Ashworth scale 32 scores not reported) Tizanidine 8 mg Smolenski Multiple Tone: Ashworth scale No significant None reported tid 77 sclerosis Spasticity: 5 point scale differences 1981 Muscle strength: 6 point scale between Baclofen 20 mg FAIR 21 Global assessment of change in interventions tid condition: Unspecified methods (Ashworth scale Tolerance to medication: scores not Unspecified methods reported) Tizanidine mean Stien Multiple Tone/spasticity: Ashworth scale No significant 6% (1/18) 23 mg/day 64 sclerosis Functional status: Kurtzke differences 1987 Expanded Disability Status Scale between 5% (1/20) Baclofen mean FAIR 40 Functional assessment: Pederson interventions 59 mg/day scale (Ashworth scale scores not reported) Tizanidine, baclofen, or dantrolene versus diazepam Tizanidine mean Bes Post-stroke or Spasticity: 5 point scale No significant 12% (6/51) 17 mg/day 78 head-trauma Functional status: walking distance differences 1988 Severity of spasms: 5 point scale between 31% (17/54) Diazepam mean FAIR 105 Muscle strength: Unspecified interventions 20 mg/day methods Clonus: Unspecified methods Tizanidine mean Rinne Multiple Spasticity: Ashworth scale No significant 0% (0/15) 14 mg/day 71 sclerosis differences 1980 (1) between 27% (4/15) Diazepam mean FAIR 30 interventions 15 mg/day (Ashworth scale scores not reported) Skeletal Muscle Relaxants Page 48 of 237 Final Report Update 2 Drug Effectiveness Review Project Table 2. Overview of head-to-head trials of skeletal muscle relaxants for spasticity Baclofen 30 Cartlidge Multiple Spasticity: Ashworth scale No significant Not clear mg/day and 60 79 sclerosis differences 1974 mg/day between FAIR 40 interventions Diazepam 15 (mean Ashworth mg/day and 30 score mg/day improvement 0. Reflexes, qid station stability, and hand coordination favor dantrolene. Baclofen versus clonidine Skeletal Muscle Relaxants Page 49 of 237 Final Report Update 2 Drug Effectiveness Review Project Table 2. Overview of head-to-head trials of skeletal muscle relaxants for spasticity Baclofen 20 mg Nance Spinal cord Spasticity: modified Ashworth scale No significant None reported qid 85 injury (1-5 scale with 0. Skeletal Muscle Relaxants Page 50 of 237 Final Report Update 2 Drug Effectiveness Review Project Table 3. Overview of placebo-controlled trials of included skeletal muscle relaxants for spasticity Trial Population Medication Quality Number enrolled Main outcomes for spasticity/tone Skeletal muscle relaxants approved for use in patients with spasticity Baclofen 86 Various spasticity Favors baclofen based on "EMG and force Basmajian 1974 FAIR 15 recordings" (p not reported) Baclofen 87 Various spasticity Favors baclofen using unspecified method (p not Basmajian 1975 FAIR 14 reported) Baclofen 88 Multiple sclerosis Favors baclofen using Ashworth scale (p not Brar 1991 FAIR 38 reported) Baclofen 89 M. Overview of placebo-controlled trials of included skeletal muscle relaxants for spasticity Trial Population Medication Quality Number enrolled Main outcomes for spasticity/tone Dantrolene 100 Upper motor neuron Spasticity not assessed Basmajian 1973 POOR disease 25 Dantrolene 101 Athetoid cerebral palsy No measurable difference using 4 point scale Chyatte 1973 FAIR (children) 18 Dantrolene 102 Various spasticity Dantrolene superior for "neurologic measurements" Denhoff 1975 FAIR (children) using unspecified methods (p<0. Overview of placebo-controlled trials of included skeletal muscle relaxants for spasticity Trial Population Medication Quality Number enrolled Main outcomes for spasticity/tone Tizanidine 115 Various spasticity No significant difference using Ashworth scale Knutsson 1982 FAIR 13 Tizanidine 116 Multiple sclerosis No significant difference using unspecified method Lapierre 1987 FAIR 66 Tizanidine 117 Various spasticity No significant difference using Penn Spasm Meythaler 2001 FAIR 17 Frequency Scale, favors tizanidine using Ashworth scale (p=0. O verview ofh ead-to-h ead trials ofskeletalm uscle relaxants form usculoskeletalconditions Interventions Study Population O verall Dose Y ear N um berenrolled M ainoutcom es assessed M ainresults with drawals Tiz anidine versus ch lorz oxaz one Tiz anidine 2 m g tid Bragstad Back spasms M uscle tension: 4 pointscale N o significantdifferences 0% (0/14) 123 Painintensity: 4 pointscale betweeninterventions 1979 C h lorz oxaz one 500 Tenderness: 4 pointscale 8% (1/13) m g tid F A IR 120 Interference with normalactivities: 4 pointscale C yclobenz aprine versus m eth ocarbam ol C yclobenz aprine 10 Preston L ocaliz ed acute M uscle spasm: 9 pointscale N o significantdifferences 14% (12/87) m g tid 20 muscle spasm L ocalpainand tenderness: 9 pointscale betweeninterventions except 1984 L imitationofnormalmotion: 9 pointscale sligh tly greaterproportionof 13% (12/94) M eth ocarbam ol F A IR 227 Interference with normalactivities: 9 pointscale patients with improvementinlocal 1500 m g qid painwith cyclobenz aprine (48% vs. O verview ofh ead-to-h ead trials ofskeletalm uscle relaxants form usculoskeletalconditions Interventions Study Population O verall Dose Y ear N um berenrolled M ainoutcom es assessed M ainresults with drawals C arisoprodol350 Boyles A cute back sprainor M uscle spasm: 5 pointscale C arisoprodolsuperiorto 10% (4/40) m g qid 129 strainwith spasms Tenderness: 5 pointscale diaz peam formuscle stiffness 1983 M obility restriction: 5 pointscale (p<0. O verview ofh ead-to-h ead trials ofskeletalm uscle relaxants form usculoskeletalconditions Interventions Study Population O verall Dose Y ear N um berenrolled M ainoutcom es assessed M ainresults with drawals C yclobenz aprine 30- Sch einer A cute back or M uscle spasm: 5 pointscale C yclobenz aprine more effective 8% (2/26) 40 m g tid 128 neck spasms Pain: 5 pointscale th andiaz epam (p<0. Overview of placebo-controlled trials of skeletal muscle relaxants for musculoskeletal conditions Population Main outcomes (included skeletal muscle relaxant Medication Trials Number enrolled versus placebo) Skeletal muscle relaxants approved for use in patients with musculoskeletal conditions Carisoprodol 138 Low back syndrome No significant difference for pain using 4 point scale, Baratta 1976 FAIR 105 carisoprodol superior to placebo for various functional measurements and for sleep Carisoprodol 139 Acute back or neck syndrome Carisoprodol superior for pain, spasm, and limitation Cullen 1976 FAIR 65 of movement using unspecified methods (all p<0. Skeletal Muscle Relaxants Page 57 of 237 Final Report Update 2 Drug Effectiveness Review Project Table 5. Overview of placebo-controlled trials of skeletal muscle relaxants for musculoskeletal conditions Population Main outcomes (included skeletal muscle relaxant Medication Trials Number enrolled versus placebo) Cyclobenzaprine Borenstein Nonspecific low back pain Cyclobenzaprine 5 mg tid superior to placebo using 5 (2. Cyclobenzaprine Borenstein Acute low back syndrome Cyclobenzaprine + naprosyn superior to naprosyn (+naprosyn in both 148 40 alone for functional capacity using 4 point scale 1990 arms) POOR (p<0.
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