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The incorporation of high-dose cytarabine for postremission therapy has substantially improved the outcome of CBF-AML patients order cialis extra dosage now, especially when administered in the setting of repetitive cycles purchase cialis extra dosage online. For many years cheap 60 mg cialis extra dosage amex, high-dose cytarabine was the standard treatment in CBF-AML resulting in favorable long-term outcome in approximately half of the patients cialis extra dosage 60 mg generic. Therefore, CBF-AML patients are generally considered to be a favorable AML group. However, a substantial proportion of patients cannot be cured by the current treatment. Additional genetic alterations discovered in CBF-AML help in our understanding of the process of leukemogenesis and some of them may refine the risk assessment in CBF-AML and, importantly, also serve as targets for novel therapeutic approaches. We discuss the clinical and genetic heterogeneity of CBF-AML, with a particular focus on the role of KIT mutations as a prognosticator, and also discuss recent efforts to target the KIT kinase in the context of existing therapeutic regimens. Introduction repetitive cycles of HiDAC compared with only one cycle was Acute myeloid leukemia (AML) with t(8;21)(q22;q22) and with the shown to reduce the risk of relapse both in t(8;21) and inv(16) AML, pericentric inversion of chromosome 16 [inv(16)(p13. The implementation AML patients above the age of 60 years harbor one of both of repetitive cycles of HiDAC for postremission treatment results in chromosome aberrations. However, several hematopoiesis providing the common designation “CBF-AML. However, because approximately one-half of patients with CBF-AML are still minor proportion of patients. In addition, there is still the open not cured, there is a need for markers to identify patients unlikely to question of how much cytarabine is enough to effectively treat respond to current treatment and to develop novel therapeutic CBF-AML without jeopardizing the outcome benefit. There is some approaches based on a better understanding of pathophysiology of evidence that less cytarabine is sufficient for an effective treatment the disease. A recent study by the HOVON/SAKK group (Dutch Belgian Cooperative Treatment and outcomes Trial Group for Hemato-Oncology/Swiss Group for Clinical Cancer Chemotherapy Research) showed similar outcome results for CBF-AML patients After anthracycline- and cytarabine-based induction chemotherapy, treated by multiagent chemotherapy incorporating cytarabine at a cumulative dose of 13. Analyses of the CBF-AML subset in this study therapy with high dose of cytarabine (HiDAC; 3 g/m2 bid on days 1, have shown similar event-free survival (EFS) and OS for patients 3, and 5) resulted in a clear survival advantage in CBF-AML treated with IDAC and HiDAC (EFS at 5 years: 58% vs 47%; OS at compared with intermediate-dose cytarabine (IDAC) or lower doses 5 years: 64% vs 67%). Based on the data we have so far, the optimal (400 or 100 mg/m2, respectively, as a continuous infusion on days 1 dose of cytarabine and number of chemotherapy courses is not to 5). Hematology 2013 209 A study from the MD Anderson Cancer Center on 114 patients with HLA-identical sibling with 132 patients treated with cytarabine- CBF-AML reported improved EFS in patients treated with fludara- based chemotherapy within 8 German AML trials. Among the 107 patients achieving a CR, was significantly higher (P. Although the OS was similar for both types of postremis- The immunoconjugate gemtuzumab ozogamicin (GO) combines an sion treatment in t(8;21) patients with the loss of a sex chromosome antibody directed against the CD33 antigen with calicheamicin, a 11 (LOS), patients without LOS treated with allogeneic SCT had a DNA-damaging toxin. Upon binding to CD33, the CD33-GO significantly higher risk of overall mortality (P. This explains why cells express- 11 compared the results of allogeneic versus autologous SCT in t(8;21) ing higher levels of CD33 are more susceptible to GO. A study by Gorin et al reported a significantly because patients with CD33-negative AML respond to treatment higher relapse incidence after autologous SCT compared with alloge- with GO, a CD33-independent endocytotic transport of the drug into 21 11 neic SCT in t(8;21) (P. GO was approved by the Food and In this study, the treatment-related mortality after allogeneic SCT was Drug Administration in the year 2000 for the treatment of significantly higher in both t(8;21) (P. A Japanese study also analysis of a following randomized trial, the drug was with- showed comparable results for OS after allogeneic and autologous SCT drawn from the market in 2010. The Medical Research Council 22 in CR1 for both t(8;21) and inv(16) AML. Overall, the addition of GO CBF-AML patients, the CR2 rate is higher (86%-97% vs 33%-78%) did not affect outcome in AML. However, in subset analyses, a and the long-term outcome after a second intensive consolidation significant survival benefit was observed in CBF-AML patients 6,7,23,24 more favorable in inv(16) AML. Relapsing CBF-AML pa- who did receive GO compared with the CBF-AML group who 13 tients who achieve a CR2 frequently undergo allogeneic SCT. The reasons However, a recent retrospective MRC study in CBF-AML patients why the beneficial effect of GO on OS was confined to this AML achieving a CR2 failed to demonstrate a survival benefit for subgroup are unclear, but the presence and degree of CD33 blast 19 allogeneic SCT compared with non-allografted patients. A Japa- positivity were revealed not to be predictive factors in this 13 nese study analyzing the outcome of CBF-AML patients undergo- study. Further studies are needed to confirm the subgroup- ing allogeneic SCT in CR2 or CR3 reported a better OS in inv(16) dependent beneficial impact of GO in CBF-AML and to elucidate than in t(8;21) AML patients (P. To date, GO has not been reapproved and in trend also a better DFS (P. These results are consistent with the data reported by clinical trials. However, the accumulated data on the efficacy of previous studies, which suggested a higher sensitivity of inv(16) GO in newly diagnosed AML, particularly in favorable-risk 6,7 AML to salvage treatment. The Japanese study also reported that, AML and in acute promyelocytic leukemia, and also on its 14 among patients not being in CR at the time of transplantation, those acceptable toxicity profile, provide a basis for its reapproval. In with inv(16) AML had a significantly better 3-year DFS (P. CBF-AML in older patients In a French study on 147 patients with t(8;21) or inv(16) age 60 Allogeneic and autologous stem cell transplantation years or older, almost 90% achieved a CR after 1 to 2 courses of Allogeneic stem cell transplantation (SCT) is generally not adminis- induction therapy. A meta-analysis of several prospective trials retained in older CBF-AML. However, the LFS at 5 years in the evaluating the impact of allogeneic SCT for AML in CR1 did not French study was only 26%. Runx1 or Cbfb allele fail to develop definitive hematopoiesis and die The main mutational clusters in CBF-AML include KIT exon 17, in utero, indicating that both CBF subunits are critical for normal which encodes the activation loop (A-loop), and exon 8, which hematopoietic development. In a results in the CBFB gene on chromosome 16q22 being fused to cytokine-dependent myeloid cell line (32D), the overexpression MYH11 on chromosome 16p13. This hypothesis is supported by studies on mouse fibroblast cell line with these KIT mutants caused ligand- knock-in embryos heterozygous for Runx1-RUNX1T1 or Cbfb- independent colony formation. The mutant developed AML with a latency of 4-5 months within the acquisition of additional genetic hits is necessary for the develop- 36,37 observation time of 1 year; AML was the only malignant ment of a leukemic phenotype. Some secondary alterations 52 hematological phenotype noticed in these animals. Genes encoding tyrosine kinases, namely KIT (v-kit Although in several but not all studies in t(8;21) AML, KIT Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) and mutations, in particular those affecting the A-loop, have been FLT3 (FMS-like tyrosine kinase), as well as N- and K-RAS associated with unfavorable outcome, the prognostic impact of guanosine triphosphatases, that is, NRAS (neuroblastoma rat sar- KIT mutations in inv(16) AML is less clear (Table 1). In inv(16) coma viral oncogene homolog) and KRAS (Kirsten rat sarcoma AML, the breakpoint variability in the MYH11 gene results at viral oncogene homolog), have been identified as frequent second- least in 10 different fusion variants, with type A fusion being ary mutations in CBF-AML. Indeed, almost 90% of AML with 53 38 39 found in 90% of the cases. One recent study in adult patients t(8;21) (Figure 1A) and more than 90% of AML with inv(16) with inv(16) AML reported for the first time that KIT mutations (Figure 1B) harbor additional secondary chromosome aberrations in exons 8 and 17 do not occur in patients with non-type A and/or mutations affecting KIT, FLT3, NRAS, and KRAS. In that study, patients with KIT muta- tions had significantly inferior EFS and OS compared with KIT patients with type A CBFB-fusion and wild-type KIT and High KIT expression is observed in hematopoietic stem cells. The KIT protein is a member relevance of mutated KIT (Table 1). Although the current data do of type III tyrosine kinases (RTK), which share a common not yet support the use of KIT mutational status in clinical protein structure consisting of 5 immunoglobulin-like domains in practice to guide clinical decision making regarding therapeutic the extracellular part, a transmembrane domain, an intracellu- interventions, testing for KIT mutations as a prognostic marker larly located juxtamembrane (JM), and a split kinase domain. Such mutations have been detected in Global gene expression studies found KIT to be highly expressed in various malignancies, including mastocytosis, gastrointestinal CBF-AML independent of its mutation status57,58 (gene expression Hematology 2013 211 Figure 1. Pie charts illustrating the genetic heterogeneity and coexistence of distinct secondary genetic abnormalities in AML with t(8;21) and inv(16). The charts are based on patients with complete cytogenetic data and complete mutation status on KIT, FLT3, NRAS, and KRAS. Among the secondary chromosome aberrations, loss of a sex chromosome ( Yor X), deletions of the long arm of chromosome 9 [del(9q)], and trisomy 8 ( 8) are indicated; all other secondary chromosome aberrations constitute one group abbreviated in the chart as “o. Among the secondary chromosome aberrations, trisomy 22 ( 22) and trisomy 8 ( 8) are indicated; all other secondary chromosome aberrations constitute one group abbreviated in the chart as o. Due to the rounding error, all values do not add up to exactly 100%. In vitro studies support subsequently treated with cytarabine and/or the TKI dasatinib. Retrospective studies assessing the prognostic relevance of KIT mutations in t(8;21) and inv(16) AML Age range, y Proportion of patients Median N (median) Analyzed KIT exons with mutated KIT,%a follow-up, y Prognostic relevance of KIT mutations Reference t(8;21) AML 146 18-73 (46) 8, 10, 11, 17 30 (44/146) 3. MVA: KIT exon 17 mutations at codon D816 significant unfavorable factor for EFS (HR 4. MVA: KIT exon 17 mutations significant unfavorable factor for EFS (HR 4. In vitro activity of selected compounds against KIT the second part of the tyrosine kinase domain (codons D835 and wild-type and distinct KIT mutants I836).

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If the client has previ- and intestinal tracts and they will only disclose these ously sought help from elsewhere purchase 40 mg cialis extra dosage, it is important to symptoms to someone they trust buy cialis extra dosage without prescription. A ‘safe’ reason for ask why she has come to the present clinic at this their visit will be invented and they will make as particular time and what her hopes for the con- rapid an exit as possible if their first impressions are sultation are cialis extra dosage 100mg. This will lead to consultations in other cause of her pain is a helpful and often revealing clinics or with traditional healers order cialis extra dosage 200mg otc, with compound- 9 question. If the pain has been present for over 6 months it Cultural, ethnic, socioeconomic, religious and is unlikely to be caused by a life-threatening illness, gender perspectives, as well as attitudes, beliefs and but this assumption should not be made. Some- biases all come to play during the consultation pro- times the sensitive nature of their symptoms deters cess, affecting both the health provider and their 8 women from seeing a health provider in a timely client. In under-resourced countries the socio- manner, especially if they have had bad experiences economic differences between health provider and in the past, heard negative stories about the health client, especially in the rural areas may be enor- service, are frightened of what may happen to mous. Even in urban areas there may be wide cul- them, or if there are cultural myths about their tural differences and beliefs and language may also symptoms that make them difficult to divulge. Involvement of an interpreter will The following are important points to clarify bring yet another dimension into the consultation. Health providers • Does anything make it better or worse? It lays the foundation for a struc- tured physical examination, after which the need Menstrual history for further investigations is determined. If possible any medical records held at the clinic should be Age at menarche and any significant menstrual read before the client enters the room. Are men- records that the client may have brought with her strual problems a current concern? The client should empty her bladder strual period and if there has been any abnormal before the physical examination, which will make bleeding since that date should be noted. Past medical, surgical and obstetric histories Abdominal examination Enquiry needs to be made about any past serious Inspection will reveal signs of previous surgery and medical illnesses, including psychiatric illness, any any obvious masses or distention. If the client is operations, HIV and sexually transmitted infec- experiencing pain prior to abdominal palpation, tions, and any pregnancies together with their out- asking her to lift her head and shoulders off the bed comes. For nulliparous women enquiry should be and enquiring whether this eases the pain or makes made about their pregnancy intentions. Are they it worse will determine whether the pain is origi- currently trying to conceive, if so, for how long nating from within the abdominal cavity or the and is failure to conceive an anxiety? Tensing the abdominal wall child is a common reason for women to make re- muscles tends to lessen intra-abdominal pain, peated visits to a health facility, especially in under- whereas the pain will be made worse if the patho- resourced countries where bearing children is 10 logy is in the abdominal wall. Abdominal palpation should commence in a Past and present contraceptive use should be re- pain-free site and proceed systematically around the corded, together with any unpleasant side-effects. Any tender areas, obvious masses It is helpful to know whether there is a history or loaded bowel should be noted. The timing of this enquiry depends on the rapport built up with the client, and it can be done Speculum examination at any appropriate time during the consultation. This is advisable for women who are sexually Although not clearly understood, there appears to active, and should always be performed if there be a relationship between chronic pelvic pain and has been post-coital bleeding, an abnormal vaginal childhood sexual abuse, especially if there is con- 6 discharge or if the client has never had their cer- tinuing abuse into adulthood. Sometimes bluish deposits of endometriosis can be seen in the posterior fornix. Cervical screening is not readily available in under- The physical examination resourced countries and many women with cervical The physical examination is important for eliciting cancer present with untreatable late-stage disease. It is also Opportunistic detection of early cervical cancer a ‘psychodynamic event’9 and the way the client gives the only chance for surgical cure when radio- responds may give an insight into the way they feel. If the cervix looks Read more on the gynecological examination in normal and vaginal inspection with acetic acid Chapter 1 if you feel unsure about the different (VIA) is a service that is locally available, informa- procedures. An explanation should be given about tion can be given to the client so that if appropriate how the examination will be conducted, starting she can attend at her convenience (see Chapter 26 with the need to perform an abdominal examina- on how to do VIA). Intimate examinations Vaginal examination are usually consented to, but they can in themselves cause much distress especially if a woman has been Inspection of the vulva will reveal signs of irrita- in an abusive relationship. The health provider tion, inflammation, ulcers, warts or discharge. Women who who has not been sexually active or anyone who decline vaginal examinations should not be made prefers not to have this done. If digital examination to feel they have compromised their chances of is declined or not tolerated, gentle examination 69 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS with a long cotton-wool bud may be agreed upon Investigations and can give useful information. Urine, stool and pregnancy testing Initial digital examination should be with one finger to minimize discomfort so that potential Simple dipstick testing of urine, preferably on a painful areas can be better localized. If well toler- midstream specimen, should be performed. If ated, two fingers can be inserted later to aid further macroscopic hematuria is present the client needs examination. Gentle palpation of the anterior further investigation, but always check she is not vaginal wall will determine any urethral or bladder menstruating! The presence of leukocytes or nitrites base tenderness. Examination of the posterior may indicate cystitis and if the client is sympto- vaginal wall and posterior fornix will reveal any matic a course of antibiotics should be prescribed tender nodules that could indicate endometriosis. If microscopic Asking the client to contract and relax her pelvic hematuria is detected the sample should be sent for floor muscles, together with gentle digital exami- microscopy to exclude schistosomiasis, and consid- nation of the muscles, can assess pain originating in eration given to testing for tuberculosis. Bimanual examination will losis can mimic almost any disease and in endemic determine the size, position, mobility or fixation areas should not be forgotten. Microscopic hema- of the uterus, whether the uterus is tender and turia is quite common and can occur after exercise whether there are any obvious adnexal masses. Before referral for more extensive investi- gations the test should be repeated twice. Urinary Additional examinations tract cancer is extremely rare in women under 4011. Other medical causes (including sickle cell disease) Women with the following signs and symptoms would be inferred from the history. Microscopy of need additional investigations and possibly referral: a stool sample should also be arranged, as parasitic • Rectal bleeding/blood in stool: proctoscopy, infections can cause abdominal/pelvic pain. A full • Pelvic or abdominal mass, including fibroids blood count with differential is a good basic test if (see Chapter 19): ultrasound and possible available. Other blood tests should be ordered de- surgery pending on the clinical findings and their local • Ascites: ultrasound and if possible cytology of availability. Abdominal dia screening or presumptive treatment for ultrasound should be used to assess the uterus and chlamydia and gonorrhea followed by reassess- ovaries in adolescents with pelvic pain, in women ment after 4 weeks who decline a vaginal examination and all women • Cervix suspicious of carcinoma: biopsy of who have an abdominal mass. Transvaginal scan- cervical lesion/urgent surgery as deemed ning is superior to abdominal scanning for visual- appropriate izing pelvic masses and is useful for detecting • Excessive weight loss: HIV test, consider poss- adenomyosis and small endometriomas that would ible malignancy indicate endometriosis, or hydrosalpinx that would 70 Chronic Pelvic Pain indicate chronic pelvic inflammatory disease. Peri- infertility, endometriosis in a first-degree relative, toneal deposits of endometriosis will not be visual- and immune disorders14. The vaginal probe can be used to identify Three different forms of endometriosis have particularly tender areas, and an experienced ultra- been described, and any mixture of lesions is sonographer is able to detect the position and possible15: mobility of the ovaries. Immobility of an ovary 12 • Peritoneal endometriosis, where endometriosis may be predictive of endometriosis or adhesions. Infertility investigations • Endometriomas, which are ovarian cysts lined Infertility is probably one of the commonest causes with endometrial-like tissue and containing a of chronic pelvic pain in under-resourced coun- thick, tarry, ‘chocolate-like’ fluid. If this is the working diagnosis, investigations between the vagina and rectum. If the client has not come with her part- small and barely visible, to lesions causing large ner she should be encouraged to return with him so ovarian cysts, extensive adhesions and sometimes that they can be seen together. The commonest infiltrating into the bowel and/or bladder. However, normally fertile women and men in under-resourced countries do not have have also been found with endometriosis. Inferti- access to the treatment options available in richer lity is to be expected when endometriosis causes countries, but compassionate management should adhesions with blockage or distortion of the fallo- instill hope, as it is rarely possible to state that a pian tubes, but for reasons not fully understood woman will never be able to conceive. The following condi- A working diagnosis of endometriosis is made from tions are the most likely to cause chronic pelvic a combination of symptoms and physical findings. It is possible for Transvaginal ultrasound if available (or abdominal more than one condition to be present in the same ultrasound in those not sexually active) may be individual: helpful, especially for diagnosing endometriomas. It is an estrogen- micturition dependent condition, with symptoms usually • Past diagnosis of irritable bowel syndrome appearing after the menarche and resolving after • Past history of ovarian cysts the menopause. Risk factors for endometriosis • Difficulty conceiving include: early age at menarche, short menstrual • Past episodes of pelvic inflammatory disease cycles, heavy menstrual flow, painful menstruation, • Sleep disturbances. They should be and increasing the dose if breakthrough bleeding offered treatment depending on whether or not occurs.

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Characteristics of head-to-head studies comparing omalizumab with placebo in children and adults cheap cialis extra dosage online master card. order cialis extra dosage with mastercard. buy generic cialis extra dosage 60 mg on-line. cialis extra dosage 50mg overnight delivery..................................................................................................................................................... Characteristics of head-to-head studies comparing ICS+LABA with ICS+LABA.................... Characteristics of head-to-head studies comparing BUD/FM for maintenance and relief (MART) with ICS/LABA for maintenance and Short-Acting Beta-Agonist (SABA) for relief.................... Characteristics of head-to-head studies comparing ICSs with LTRAs in children and adults. Characteristics of head to head studies comparing ICSs with LTRAs in children < 12........... Characteristics of head-to-head studies comparing ICSs with LABAs.................................... Characteristics of head-to-head studies comparing leukotriene modifiers with LABAs for monotherapy............................................................................................................................................. Characteristics of head-to-head studies comparing ICS+LABA with ICS alone as first line therapy in children and adults.................................................................................................................. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher dose ICS.............................................................................................................................. Characteristics of head-to-head studies comparing ICS+LABA compared with same dose ICS.......................................................................................................................................................... Characteristics of head-to-head studies comparing ICS + LTRA with ICS............................ Characteristics of head-to-head studies comparing ICS+LABA with leukotriene modifiers.. Characteristics of head-to-head studies comparing ICS+LABA with ICS+leukotriene modifiers................................................................................................................................................. Characteristics of head-to-head studies comparing ICS+LABA with LTRA+LABA............... Summary of studies on posterior subcapsular cataracts....................................................... Summary of studies on ocular hypertension or open-angle glaucoma.................................. Tolerability and frequency of adverse events results from systematic reviews comparing ICS+LABA with ICS+LABA..................................................................................................................... Summary of studies evaluating subgroups of patients for whom asthma controller medications may differ in efficacy or frequency of adverse events............................................................................ Summary of the evidence by key question for controller medications for the treatment of persistent asthma in adolescents/adults ≥ 12 years of age and children < 12 years of age.................. References throughout this report identify the respective documents as Evidence Tables A or B. Controller medications for asthma 7 of 369 Final Update 1 Report Drug Effectiveness Review Project Suggested citation Jonas DE, Wines R, DelMonte M, Amick H, Wilkins T, Einerson B, Schuler CL, Wynia BA, Bryant Shilliday B. Drug class review: Controller medications for asthma. Morgan, MA, Patricia Thieda Keener, MA, and Daniel Reuland, MD, MPH for their expertise and contributions toward creating the original controller medications for asthma report. We also thank Irvin Mayers, MD, FRCPC, University of Alberta and Allan Luskin, MD, University of Wisconsin who served as clinical advisors and provided their thoughtful advice and input during the research process for the original report. Finally, we thank Claire Baker, Shannon Brode, Elizabeth Harden, and Megan Van Noord for their invaluable assistance with data abstraction, literature searches, and data entry. Funding The Drug Effectiveness Review Project, composed of 12 organizations including 11 state Medicaid agencies, and the Canadian Agency for Drugs and Technology in Health commissioned and funded for this report. These organizations selected the topic of the report and had input into its Key Questions. The content and conclusions of the report were entirely determined by the Evidence-based Practice Center researchers. The authors of this report have no financial interest in any company that makes or distributes the products reviewed in this report. Controller medications for asthma 8 of 369 Final Update 1 Report Drug Effectiveness Review Project INTRODUCTION Asthma is a chronic lung disease characterized by reversible airway obstruction, inflammation, and increased airway responsiveness. As a result of inflammation, individuals with asthma may experience symptoms such as wheezing, difficulty breathing, or coughing. The airway obstruction which occurs with asthma is generally reversible spontaneously or with treatment. Asthma is thought to have a genetic, inheritable component, often begins early in life, and 1 consists of variable symptoms regardless of asthma classification. The Expert Panel of the National Asthma Education and Prevention Program (NAEPP) recently reclassified asthma categories; the mild intermittent category was eliminated (now called intermittent) and the 1 persistent category was subdivided into mild, moderate, or severe. The change was partly done to acknowledge that exacerbations can be severe in any asthma category. Table 1 lists the criteria used to classify asthma severity. Classification of asthma Short-Acting Interference FEV1 Daytime Nighttime Beta-2 Agonist with daily % symptoms symptoms use activity predicted FEV1/FVC ≤ 2 ≤ 2 Intermittent ≤ 2 days/week None > 80% Normal days/week nights/month Persistent > 2/week but 3-4 > 2 days/week Minor ≥ 80% Normal Mild < 1/day nights/month > 1 night/week > 60% - < Reduced Moderate Daily Daily Some but < 1/night 80% 5% Severe Several times Reduced > Continual Frequent Extreme ≤ 60% daily 5% Asthma outcomes have improved over the past several years but the burden remains substantial. Asthma is estimated to affect 300 million individuals worldwide with 22 million of 2-4 those individuals being in the US. It is the cause of 250,000 worldwide deaths annually with 2-4 4,000 of them in the US. The World Health Organization estimates 15 million disability- 2 adjusted life years (DALYs) lost annually due to asthma. In 2005, there were 488,594 hospital discharges in the US, 12. Many current medications available to treat persistent asthma target the inflammatory process caused by multiple inflammatory cells and mediators including lymphocytes, mast cells, 1 eosinophils, among others. There are currently two categories of medications used in asthma treatment: controller medications and quick relief (or rescue) medications. Although all patients with persistent asthma should have a short-acting relief medication on hand for treatment of exacerbations and a controller medication for long-term control, this report will focus on the following currently available controller medications: inhaled corticosteroids (ICSs), Long-Acting Controller medications for asthma 9 of 369 Final Update 1 Report Drug Effectiveness Review Project Beta-2 Agonists (LABAs), leukotriene modifiers, anti-IgE medications, and combination products. Inhaled corticosteroids are the preferred agents for long-term control of persistent asthma 1 according to expert panel recommendations. The inhaled route of administration serves to directly target the inflammation while minimizing systemic effects which can result from oral administration. These agents act via anti-inflammatory mechanisms and have been approved as 1 first line therapy for asthma control in all stages of persistent asthma. The 7 ICSs currently available include: beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate, mometasone furoate, and triamcinolone acetonide. Table 2 lists the trade names, manufacturers, available formulations, and age indications for controller medications for persistent asthma. Although it is not approved for the treatment of asthma and thus is not ® included in Table 2, tiotropium (Spiriva ) was included in this report to determine if there is any published evidence for its use in people with asthma. Dulera (mometasone/formoterol), now approved for treatment of asthma in people >12 years, is not included in this report because it was approved after our cutoff date for the inclusion of new medications. Controller medications for asthma 10 of 369 Final Update 1 Report Drug Effectiveness Review Project 1, 5-10 Table 2. Long-term controller medication class, trade names, manufacturers, formulations, and indications Dosage Approved indication Medication class Generic name Trade name Manufacturer form/device Strength in US and Canada 40 mcg/puff a ® 50 mcg/puff Asthma (age ≥ 5) QVAR Ivax HFA Beclomethasone 80 mcg/puff a dipropionate 100 mcg/puff ®b 42 mcg/puff Asthma (age ≥ 5) Vanceril Schering MDI 84 mcg/puff Pulmicort 90 mcg/dose ®c AstraZeneca DPI Flexhaler 180 mcg/dose Asthma (age ≥ 6) 100 mcg/dose Pulmicort ®a AstraZeneca DPI 200 mcg/dose Turbuhaler 400 mcg/dose Budesonide 0. Long-term controller medication class, trade names, manufacturers, formulations, and indications Dosage Approved indication Medication class Generic name Trade name Manufacturer form/device Strength in US and Canada 100 mcg/dose 250 mcg/dose a 500 mcg/dose Asmanex 110 mcg/dose Asthma (age ≥ 4) Mometasone furoate ®c Schering DPI Twisthaler 220 mcg/dose Triamcinolone ®b MDI – with spacer Asthma (age ≥ 6) Azmacort Abbot 75 mcg/dose acetonide mouthpiece Leukotriene Tablets 10 mg ® Asthma (age ≥ 1) modifiers Montelukast Singulair Merck Chewable tablets 4 mg, 5 mg Granules 4 mg/packet Leukotriene Asthma (age ≥ 5 yrs in c receptor ® 10 mg Zafirlukast Accolate AstraZeneca Tablets US); (age ≥ 12 yrs in antagonists 20 mg Canada) ®c Tablets Zyflo 600 mg Asthma (age ≥ 12 yrs) 5-lipoxygenase Zileuton ®c Critical Therapeutics Extended release Zyflo CR 600 mg Inhibitor tablets ®c Not approved for Arformoterol Brovana Sunovion Inhalation solution 15 mcg/2ml asthma (COPD only) ®c Asthma (age ≥ 5 yrs) Foradil Aerolizer Schering DPI 12 mcg/capsule Novartis ®a Foradil Pharmaceuticals DPI 12 mcg/capsule Asthma (age > 6 yrs) Formoterol fumarate/ Canada Inc. Long-Acting Beta- Eformoterol 2 Agonists Oxeze 6 mcg/capsule Asthma (age ≥ 6 yrs) ®a AstraZeneca (Canada) DPI Turbuhaler 12 mcg/capsule ®f 6 mcg/puff Oxis Turbohaler Astra Pharmaceuticals DPI Asthma (age ≥ 6 yrs) 12 mcg/puff ® Serevent Diskus GlaxoSmithKline DPI 50 mcg/blister Asthma (age ≥ 4 yrs) Salmeterol xinafoate Serevent Asthma (age ≥ 4 yrs) ®a GlaxoSmithKline DPI 50 mcg/blister Diskhaler Genentech (US) Powder for 202. Long-term controller medication class, trade names, manufacturers, formulations, and indications Dosage Approved indication Medication class Generic name Trade name Manufacturer form/device Strength in US and Canada 100mcg/50mcg ® GlaxoSmith Asthma (age ≥ 4 yrs) Advair Diskus DPI 250mcg/50mcg Kline 500mcg/50mcg Fluticasone 45mcg/21mcg ®c GlaxoSmith Asthma (age ≥ 12 yrs) propionate/ Advair HFA HFA 115mcg/21mcg Kline Salmeterol xinafoate 230mcg/21mcg 50 mcg/25 mcg ®a GlaxoSmith Asthma (age ≥ 12 yrs) Advair HFA 125mcg/25mcg Combination Kline g 250mcg/25mcg products ®c 80mcg/4. Note: Unless otherwise noted, the products are available in both the US and Canada a This product is available in Canada only. Controller medications for asthma 13 of 369 Final Update 1 Report Drug Effectiveness Review Project Inhaled corticosteroids are delivered through a variety of devices including metered dose inhalers (MDIs), dry powder inhalers (DPIs), or nebulizers.

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A randomized order cialis extra dosage from india, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo in preventing 2 postoperative nausea and vomiting over a 72-hour period buy 100mg cialis extra dosage amex. Scheduled prophylactic ondansetron administration did not improve its antiemetic efficacy after 2 intracranial tumour resection surgery in children purchase cialis extra dosage 100 mg with visa. Coronary vasospasm leading to an acute myocardial infarction after the administration of dolasetron cheap cialis extra dosage 40 mg amex. Antiemetics Page 135 of 136 Final Report Update 1 Drug Effectiveness Review Project Exclusion Excluded studies code # Einhorn LH, Brames, M. Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea adn vomiting in patients receiving multiple- 6 day cisplatin chemotherapy for germ cell cancer. Hasler SB, Hirt A, Ridolfi Luethy A, Leibundgut KK, Ammann RA. Safety of ondansetron loading doses in children with cancer. A phase II trial of olanzapine and palonosetron for the prevention of chemotherapy induced nausea and 3 vomiting: a Hoosier oncology group study. Economic evaluation of ondansetron vs dimenhydrinate for prevention of postoperative vomiting in 2 children undergoing strabismus surgery. Placental transfer of ondansetron during early 3 human pregnancy. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents [Systematic Review]. Drugs for preventing postoperative nausea and vomiting [Systematic Review]. Meta-analysis of its effectiveness in patients with previous history of 6 postoperative nausea and vomiting. Gupta A, Wu CL, Elkassabany N, Krug CE, Parker SD, Fleisher LA. Does the routine prophylactic use of antiemetics affect the incidence of postdischarge 6 nausea and vomiting following ambulatory surgery? Huang JQ, Zheng GF, Chan GC, Karlberg J, Lam SK, Wong BC. Efficacy of current antietmetic treatment for preventing delayed chemotherapy-induced 6 nausea and vomiting: a meta-analysis of randomized controlled trials. The efficacy of 5-HT3 receptor antagonists for the prevention of postoperative nausea and vomiting after craniotomy: a 6 meta-analysis. Antiemetics Page 136 of 136 Drug Class Review Newer Antiemetics Final Report Update 1 Evidence Tables January 2009 The purpose of this report is to make available information regarding the comparative effectiveness and safety profiles of different drugs within pharmaceutical classes. Reports are not usage guidelines, nor should they be read as an endorsement of, or recommendation for, any particular drug, use, or approach. Oregon Health & Science University does not recommend or endorse any guideline or recommendation developed by users of these reports. Kimberly Peterson, MS Marian McDonagh, PharmD Susan Carson, MPH Sujata Thakurta, MPA: HA Oregon Evidence-based Practice Center Oregon Health & Science University Mark Helfand, MD, MPH, Director Copyright © 2008 by Oregon Health & Science University Portland, Oregon 97239. Final Report Update 1 Drug Effectiveness Review Project TABLE OF CONTENTS Evidence Table 1. Chemotherapy: Head-to-head trials………………………………………………3 Evidence Table 2. Quality assessments of chemotherapy head-to-head trials…………………139 Evidence Table 3. Quality assessments of chemotherapy placebo-controlled trials………….. Chemotherapy: Active-control trials……………………………………………255 Evidence Table 6. Quality assessment for chemotherapy active-control trials…………………276 Evidence Table 7. Quality assessments of the radiation controlled-clinical trials………………299 Evidence Table 9. Prevention of postoperative nausea and vomiting: Head-to-head trials…... Quality assessment of the head-to-head trials for the prevention of postoperative nausea and vomiting…………………………………………………………………. Prevention of postoperative nausea and vomiting: Active-control and placebo-controlled trials………………………………………………………………………………. Quality assessment of active-control and placebo-controlled trials for prevention of postoperative nausea and vomiting…………………………………………………. Treatment of established postoperative nausea and vomiting: Systematic reviews…………………………………………………………………………………………………. Treatment of established postoperative nausea and vomiting: Comparative clinical trials……………………………………………………………………………………………. Quality assessments of the comparative clinical trials of treatment of established postoperative nausea and vomiting……………………………………………………482 Evidence Table 16. Long term uncontrolled intervention studies of safety and adverse events…………………………………………………………………………………………………... Quality assessment of long term uncontrolled intervention studies of safety and adverse events…………………………………………………………………………………… 492 Note: A scan of the medical literature relating to the topic is done periodically (see the Drug Effectiveness Review Project website at http://www. The Drug Effectiveness Review Project governance group elected to proceed with another update of this report. Please see the timeline on the DERP website for details on the date of its release. Prior versions of this report can be accessed at the DERP website. Antiemetics Page 2 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity C h ildren Jaing granisetronpo0. N R 5 Antiemetics Page 3 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Screened/ W ith drawn/ Setting Eligible/ L ostto fu/ H esketh rating Enrolled A nalyz ed O th erpopulationch aracteristics C h ildren Jaing 2004 35/33/33 0/0/33 Acutelym phoblastic leukem ia:100% M ulticenter 3 F orni 2000 N R /N R /90 N R /0/90 N R N otspecified 5 Antiemetics Page 4 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults C h ildren G ranisetronvsO ndansetron Jaing Com pleteresponse:noem etic episodesandnoneedforrescuem edication: 2004 W ithin24h:60. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents C h ildren Jaing 2004 "Them ostfrequentlyreportedAE swerem ildheadacheandconstipation. N oconcom itantantiem etic therapyapartfrom thestudydrugswasgivento M ulticenter TheAE swerethesam einboth groups. W ithdrawaldata:N o casesof dosereductionof antiblastics;in2ptstheifosfam ide(ifo)cycle wasstopped(ondays4& 5of infusion)becauseof neurotox icity. In N otspecified HeadachewastheonlyAE theauthorsreported;theystatedthatitwasof cisplatin-Adriam ycincyclesthecom pleteprotection(CP)ratedecreased 5 m ildintensityanditsfrequencywasthesam einall3treatm entgroups. O nthethirddaywhenAdriam ycinwas given,thetotalprotection= 44% (P<0. CP wasachievedin 19% onlyforonetypeof chem ocycle;therem aining 71% ex perienced em esisinboth cyclesforatleast1day. Antiemetics Page 6 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity Sepulveda- M eanage:11years Vildosola 2 R CT,D B, O ndansetronIV 8m g/m R ange:2-15 2008 N one N R N R /N R Parallel PalonosetronIV 0. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Screened/ W ith drawn/ Setting Eligible/ L ostto fu/ H esketh rating Enrolled A nalyz ed O th erpopulationch aracteristics Sepulveda- Vildosola Previoustreatm entwith chem otherapy:86% 2008 N R /N R /100 N R /N R /100 N auseaorvom iting inpreviouschem otherapy:76% SingleCenter 2-5 Antiemetics Page 8 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults PalonosetronvsO ndansetron Com pletecontrolof em etic eventsatday1:92% vs72% Com pletecontrolof em etic eventsatday2:72% vs46% Com pletecontrolof em etic eventsatday3:78% vs54% Com pletecontrolof em etic eventsatday4:88% vs84% Sepulveda- Com pletecontrolof em etic eventsatday5:98% vs90% Vildosola Com pletecontrolof em etic eventsatday6:100% vs94% 2008 Com pletecontrolof em etic eventsatday7:100% vs96% SingleCenter 2-5 Absenceof nauseaatday1:74% vs38% Absenceof nauseaatday2:62% vs18% Absenceof nauseaatday3:72% vs30% Absenceof nauseaatday4:88% vs58% Absenceof nauseaatday5:98% vs88% Absenceof nauseaatday6:98% vs92% Absenceof nauseaatday7:98% vs94% Antiemetics Page 9 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents Sepulveda- Vildosola 2008 N R SingleCenter 2-5 Antiemetics Page 10 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity W h ite D ex am ethasone2-4m g 8 2000 D BR CT O ndansetroniv 5m g/m 2 Children,kinetosis powasgivenalong with N o/N R 58%m ale M ulticenter Parallel O ndansetronpo 8m g studyantiem etics N R 4,5 Antiemetics Page 11 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Screened/ W ith drawn/ Setting Eligible/ L ostto fu/ H esketh rating Enrolled A nalyz ed O th erpopulationch aracteristics W h ite M eanweight(+/-SD )= 28. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults O ndivvsO ndpo Com pletecontrolof em esis(0episodes) Treatm entphaseA:73% vs71%,N S O verall(A+B):62% vs62%,N S Treatm entD ay1:81% vs78%,N S M ajorcontrolof em esis(1-2episodes): Treatm entA:16% vs17%,N S W h ite O verall(A+B):23% vs20%,N S 2000 Treatm entD ay1:10% vs13%,N S M ulticenter M ildN ausea 4,5 Treatm entD ay1:21% vs21%,N S PhaseA (alittlebitnauseous):26% vs26%,N S O verall(A+B):36% vs33%,N S N onauseaex perienced: Treatm entD ay1:73% vs70%,N S O verall(PhasesA +B):52% vs56%,N S PhaseA:64% vs64%,N S % with reducedappetiteduring treatm ent:increasedby7% from baselinevsincreasedby12% from baseline,N S Antiemetics Page 13 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents O ndpoadm inisteredasanoralsyrup,notatablet. Studym edication adm inisteredduring 2phases:phasesA andB.

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Prophylactic antiemetic therapy with granisetrondroperidol combination in patients undergoing laparoscopic 2 cholecystectomy cheap 50mg cialis extra dosage. Comparison of granisetron and droperidol in the prevention of vomiting after strabismus surgery or 2 tonsillectomy in children order generic cialis extra dosage on line. Prevention of PONV with granisetron order 100 mg cialis extra dosage otc, droperidol or metoclopramide in patients with postoperative 2 emesis discount 100mg cialis extra dosage otc. Antiemetics Page 94 of 136 Final Report Update 1 Drug Effectiveness Review Project Exclusion Excluded Studies code # Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Prophylactic oral antiemetics for preventing postoperative nausea and vomiting: Granisetron versus 2 domperidone. Prevention of post-operative nausea and vomiting with combined granisetron and droperidol in women undergoing 2 thyroidectomy. Ramosetron vs granisetron for the prevention of postoperative nausea and vomiting after laparoscopic 2 cholecystcctomy. Comparison of ramosetron and granisetron for preventing postoperative nausea and vomiting after 2 gynecologic surgery. Prophylactic therapy with combined granisetron and dexamethasone for the prevention of post-operative vomiting 2 in children. Combination of granisetron and droperidol for the prevention of vomiting after paediatric strabismus surgery. Combination of granisetron and droperidol in the prevention of nausea and vomiting after middle ear surgery. Anti-emetic efficacy of prophylactic gtanisetron compared with perphenazine for the prevention of post-operative 2 vomiting in children. Granisetron/dexamethasone combination for reducing nausea and vomiting during and after spinal 2 anesthesia for cesarean section. Prophylactic therapy with granisetron in the prevention of vomiting after paediatric surgery. A randomized, double-blind comparison 2 with droperidol and metoclopramide. Comparison of granisetron, droperidol, and metoclopramide for prevention of postoperative vomiting in children with a 2 history of motion sickness undergoing tonsillectomy. Comparison of granisetron and ramosetron for the prevention of nausea and vomiting after thyroidectomy. Ramosetron compared with granisetron for the prevention of vomiting following strabismus surgery in children. Treatment of vomiting after paediatric strabismus surgery with granisetron, droperidol, and metoclopramide. Antiemetics Page 95 of 136 Final Report Update 1 Drug Effectiveness Review Project Exclusion Excluded Studies code # Fujii Y, Tanaka H, Kawasaki T. Randomized clinical trial of granisetron, droperidol and metoclopramide for the treatment of nausea and vomiting 2 after laparoscopic cholecystectomy. A comparison of granisetron, droperidol, and metoclopramide in the treatment of established nausea and vomiting after 2 breast surgery: A double-blind, randomized, controlled trial. Benefits and risks of granisetron versus ramosetron for nausea and vomiting after breast surgery: a randomized, 2 double-blinded, placebo-controlled trial. Prevention of nausea and vomiting after middle ear surgery: Granisetron versus ramosetron. Granisetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting after 2 thyroidectomy. The effects of dexamethasone on antiemetics in female patients undergoing gynecologic surgery. Granisetron reduces the incidence and severity of nausea and vomiting after laparoscopic cholecystectomy. Prevention of nausea and vomiting with granisetron, droperidol and metoclopramide during and after spinal 2 anaesthesia for caesarean section: A randomized, double-blind, placebo- controlled trial. Prevention of nausea and vomiting in female patients undergoing breast surgery: A comparison with granisetron, 2 droperidol, metoclopramide and placebo. Prevention of PONV granisetron, droperidol and metoclopramide in female patients with history of motion sickness. Prophylactic antiemetic therapy with a combination of granisetron and dexamethasone in patients undergoing 2 middle ear surgery. A granisetron-droperidol combination prevents postoperative vomiting in children. Granisetron-droperidol combination for the prevention of postoperative nausea and vomiting in female patients 2 undergoing breast surgery. Antiemetics Page 96 of 136 Final Report Update 1 Drug Effectiveness Review Project Exclusion Excluded Studies code # Fujii Y, Toyooka H, Tanaka H. Prevention of postoperative nausea and vomiting with a combination of granisetron and droperidol. Prevention of postoperative nausea and vomiting in female patients during menstruation: Comparison of droperidol, 2 metoclopramide and granisetron. Prophylactic anti-emetic therapy with granisetron, droperidol and metoclopramide in female patients undergoing 2 middle ear surgery. Double-blind, randomized comparison of ondansetron and intraoperative propofol to prevent 2 postoperative nausea and vomiting. Progress in the control of acute and delayed emesis induced 2 by cisplatin. Gebbia V, Testa A, Valenza R, Cannata G, Tirrito ML, Gebbia N. Oral granisetron with or without methylprednisolone versus metoclopramide plus methylprednisolone in the management of delayed nausea and vomiting 2 induced by cisplatin-based chemotherapy: A prospective randomized trial. Substance P (neurokinin-1) antagonist prevents postoperative vomiting after abdominal hysterectomy 2 procedure. Antiemetic effects of granisetron, droperidol and dexamethasone in otologic surgery. Goldschmidt H, Salwender H, Egerer G, Kempe R, Voigt T. Comparison of oral itasetron with oral ondansetron: Results of a double- blind, active- controlled phase II study in chemotherapy-naive patients receiving 2 moderately emetogenic chemotherapy. Ondansetron is no more effective than supplemental intraoperative oxygen for prevention of postoperative nausea 2 and vomiting. Comparison of cyclizine and ondansetron for the prevention of postoperative nausea and vomiting in 2 laparoscopic day-case gynaecological surgery. Grond S, Lynch J, Diefenbach C, Altrock K, Lehmann KA. Comparison of ondansetron and droperidol in the prevention of nausea and vomiting after 2 inpatient minor gynecologic surgery. The effect of ginger and ondansetron on nausea and vomiting after middle ear surgery. Antiemetics Page 97 of 136 Final Report Update 1 Drug Effectiveness Review Project Exclusion Excluded Studies code # Hahlen K, Quintana E, Pinkerton CR, Cedar E. A randomized comparison of intravenously administered granisetron versus chlorpromazine plus 2 dexamethasone in the prevention of ifosfamide-induced emesis in children. A single-blind comparison of intravenous ondansetron, a selective serotonin antagonist, with intravenous metoclopramide in the prevention of nausea and vomiting associated with 2 high-dose cisplatin chemotherapy. Handberg J, Wessel V, Larsen L, Herrstedt J, Hansen HH. Randomized, double-blind comparison of granisetron versus granisetron plus prednisolone 2 as antiemetic prophylaxis during multiple-day cisplatin- based chemotherapy. Ondansetron versus primperan in treating nausea and vomiting for chemotherapy coordinated with cisplatin or 2 doxorubicin: 311 phase II clinical randomized controlled trial. Stability of cisplatin and ondansetron hydrochloride in admixtures for continuous infusion. Single-agent oral granisetron for the prevention of acute cisplatin- induced emesis: A double-blind, randomized comparison with granisetron 2 plus dexamethasone and high-dose metoclopramide plus dexamethasone. Heron JF, Goedhals L, Jordaan JP, Cunningham J, Cedar E. Oral granisetron alone and in combination with dexamethasone: A double-blind randomized comparison against high-dose metoclopramide plus 2 dexamethasone in prevention of cisplatin-induced emesis. Granisetron oral phase III clinical trial - Study on the inhibitory effect of granisetron for nausea/vomiting induced by 4 chemotherapy for tumors in the hematopoietic organs. The antiemetic efficacy and safety of granisetron compared with metoclopramide plus dexamethasone in patients receiving fractionated chemotherapy over 5 days.

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