By J. Konrad. Spartanburg Methodist College.
Interventions Included interventions are listed in Table 2 buy cheap doxepin online. Included interventions Drug Trade name Formulations a Aprepitant/fosaprepitant Emend injectable buy doxepin 25 mg on line, oral Dolasetron Anzemet injectable purchase discount doxepin line, oral Granisetron Kytril injectable, oral Ondansetron Zofran , generics injectable, oral, orally disintegrating tablet a a Palonosetron Aloxi injectable, oral a Not available in Canada Effectiveness outcomes Treatment of established postoperative nausea and/or vomiting • Success: Absence of vomiting and/or retching in a nauseated or vomiting and/or retching patient o Early: Within or close to 6 hours after surgical procedure o Late: Within or close to 24 hours after surgical procedure • Success: Absence of any emetic event (nausea, vomiting, retching) o Early: Within or close to 6 hours after surgical procedure o Late: Within or close to 24 hours after surgical procedure Antiemetics Page 9 of 136 Final Report Update 1 Drug Effectiveness Review Project • Other: Patients’ satisfaction or quality of life, number of vomiting and/or retching episodes, degree of nausea, need for rescue medications, serious emetic sequelae, delay until first emetic episode, number of emesis-free days Prevention of postoperative nausea and/or vomiting • Success: Absence of vomiting and/or retching in the postoperative period o Acute: Within or close to 6 hours after surgical procedure o Late: Within or close to 24 hours after surgical procedure • Success: Absence of any emetic event (nausea, vomiting and/or retching, or nausea and vomiting and/or retching) in the postoperative period o Acute: Within or close to 6 hours after surgical procedure o Late: Within or close to 24 hours after surgical procedure • Other: Patients’ satisfaction or quality of life, number of vomiting and/or retching episodes, degree of nausea, need for rescue medications, serious emetic sequelae, delay until first emetic episode, number of emesis-free days Prevention of nausea and/or vomiting related to chemotherapy • Success: Absence of vomiting and/or retching o Acute: During the first 24 hours of chemotherapy administration Vomiting and/or retching induced by highly emetic chemotherapy Vomiting and/or retching induced by moderately emetic chemotherapy o Late: After the first 24 hours of chemotherapy administration Vomiting and/or retching induced by highly emetic chemotherapy Vomiting and/or retching induced by moderately emetic chemotherapy • Success: Absence of any emetic event (nausea, vomiting, retching) o Acute: During the first 24 hours of chemotherapy administration Emetic event induced by highly emetic chemotherapy Emetic event induced by moderately emetic chemotherapy o Late: After the first 24 hours of chemotherapy administration Emetic event induced by highly emetic chemotherapy Emetic event induced by moderately emetic chemotherapy • Other: Patients’ satisfaction or quality of life, number of vomiting and/or retching episodes, degree of nausea, need for rescue medications, serious emetic sequelae, worst day nausea/vomiting and/or retching, delay until first emetic episode, number of emesis- free days Prevention of radiation-induced nausea and/or vomiting • Success: Absence of vomiting and/or retching o Acute: During the first 24 hours of onset of radiation therapy o Delayed: After the first 24 hours of onset of radiation therapy or after consecutive radiation therapy doses given during several days • Success: Absence of any emetic event (nausea, vomiting, retching) o Acute: During the first 24 hours of onset of radiation therapy o Delayed: After the first 24 hours of onset of radiation therapy or after consecutive radiation therapy doses given during several days Antiemetics Page 10 of 136 Final Report Update 1 Drug Effectiveness Review Project • Other: Patients’ satisfaction or quality of life, number of vomiting and/or retching episodes, degree of nausea, or need for rescue medications, serious emetic sequelae, worst day nausea/vomiting and/or retching, delay until first emetic episode, number of emesis-free days Treatment of nausea and/or vomiting associated with pregnancy (including hyperemesis gravidarum) • Success: Absence of vomiting and/or retching in a nauseated or vomiting and/or retching pregnant woman • Success: Absence of any emetic event (nausea, vomiting, retching) • Change in Rhodes index or visual analog scale assessments of symptom severity • Fetal outcome • Other: Patients’ satisfaction or quality of life, number of vomiting and/or retching episodes per period of time, need for rescue medications, serious emetic sequelae, number of emesis-free days, number of episodes and duration of hospitalization Wherever possible, data on effective dose range, dose response, and duration of therapy (time to success) will be evaluated within the context of comparative effectiveness. Harms • Overall adverse events • Specific adverse events (headache, constipation, dizziness, sedation, etc) • Withdrawals due to adverse events • Serious adverse events reported Study designs • For effectiveness, controlled clinical trials and good-quality systematic reviews. The benefit of the randomized controlled trial design is the ability to obtain a reliably unbiased estimate of treatment effects in a controlled setting. This is accomplished by using randomization 14, to produce groups that are comparable based on both known and unknown prognostic factors. Observational studies are thought to have greater risk of introducing bias, although they typically reflect effects in a broader section of the overall patient population. While some observational studies and randomized controlled trials of the same treatments have similar findings, there are also multiple examples of situations where this 16, 17 has not been true; the question of what type of evidence is best has not been resolved. While randomized controlled trials also provide good evidence on short-term adverse events, observational designs are useful in identifying rare, serious adverse events, which often require large numbers of patients exposed to a treatment over longer periods of time to be identified. Antiemetics Page 11 of 136 Final Report Update 1 Drug Effectiveness Review Project METHODS Literature Search To identify relevant citations for the original report, we searched the Cochrane Central Register th of Controlled Trials (4 Quarter 2004), Cochrane Database of Systematic Reviews, MEDLINE nd (1966 to week 1 of February 2005), EMBASE (2 Quarter 2005), and CancerLit (1974 to March 2005) using terms for included drugs, indications, and study designs (see Appendix D for complete search strategies). For update 1, we searched Medline (1996 to week 2 of 2008), nd Cochrane Central Register of Controlled Trials (2 Quarter 2008), Cochrane Database of st Systematic Reviews (1 Quarter 2008), and Database of Abstracts of Reviews of Effects (DARE) nd rd (2 Quarter 2008). These searches were repeated in October 2008 in Medline and 3 Quarter 2008 in Cochrane and DARE Databases to identify any additional publications published before the draft report was finalized. We have attempted to identify additional studies through searches of reference lists of included studies and reviews, the Food and Drug Administration website, and dossiers submitted by pharmaceutical companies for the current review. All citations were imported into an electronic database (EndNote XI). Study Selection Using the criteria listed above, two reviewers independently assessed abstracts of citations identified from literature searches for inclusion, Full-text articles of potentially relevant abstracts were retrieved, and a second review for inclusion was conducted by reapplying the inclusion criteria. Data Abstraction The following data were abstracted from included trials: study design; setting; population characteristics (including sex, age, ethnicity, diagnosis); eligibility and exclusion criteria; interventions (dose and duration); comparisons; numbers screened, eligible, enrolled, and lost to follow-up; method of outcome ascertainment; and results for each outcome. We recorded intention-to-treat results when reported. In cases where only per protocol results were reported, we calculated intention-to-treat results if the data for these calculations were available. In trials with crossover, outcomes for the first intervention were recorded if available. This approach controlled for the potential for biased results caused by differential withdrawal before crossover and for the possibility of either a “carryover effect” (from the first treatment) in studies without a washout period or a “rebound effect” from withdrawal of the first intervention. Data abstracted from observational studies included design; eligibility criteria; duration; interventions; concomitant medication; assessment techniques; age, gender, and ethnicity; number of patients screened, eligible, enrolled, withdrawn, or lost to follow-up; number of patients analyzed; and results. Validity Assessment We assessed the internal validity (quality) of trials with the predefined criteria listed in Appendix E. These criteria are based on the US Preventive Services Task Force and the National Health 18, 19 Service Centre for Reviews and Dissemination (United Kingdom) criteria. We rated the Antiemetics Page 12 of 136 Final Report Update 1 Drug Effectiveness Review Project internal validity of each trial based on the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to follow-up; and the use of intention-to-treat analysis. Trials that had a fatal flaw were rated “poor-quality”; trials that met all criteria were rated “good-quality”; the remainder were rated “fair-quality. A poor-quality trial is not valid—the results are at least as likely to reflect flaws in the study design as the true difference between the compared drugs. A fatal flaw is reflected by failure to meet combinations of items of the quality assessment checklist. External validity of trials was based on whether the publication adequately described the study population, how similar patients were to the target population in whom the intervention would be applied, and whether the treatment received by the control group was reasonably representative of standard practice. Overall quality ratings for an individual study were based on internal and external validity ratings for that trial. A particular randomized trial might receive 2 different ratings: 1 for effectiveness and another for adverse events. The overall strength of evidence for a particular key question reflects the quality, consistency, and power of the set of studies relevant to the question. Included systematic reviews were also rated for quality based on predefined criteria (see Appendix E) based on clear statement of the questions(s) and inclusion criteria, adequacy of search strategy, validity assessment and adequacy of detail provided for included studies, and appropriateness of the methods of synthesis. Data Synthesis We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies. Trials that evaluated 1 newer antiemetic against another provided direct evidence of comparative effectiveness and adverse event rates. In theory, trials that compare newer antiemetic to other drug classes or placebos can also provide evidence about effectiveness.
Replacement of sickle RBCs with transfused RBCs decreases intravascular hemolysis (grey) and hence decreases iron clearance through hemopexin and haptoglobin by the liver and leaves less free Hb available for kidney uptake and urinary loss order doxepin with a visa. Erythropoiesis of sickle RBCs is also suppressed if that transfusion regime increases the Hb order 10 mg doxepin. A greater proportion of iron turnover is through extravascular RBC destruction cheap doxepin 75mg online, which is subsequently directed via Tf to BM and hepatocytes. Increased Hb values after transfusion decrease erythropoiesis and transferrin iron clearance in BM: a greater proportion of transferrin iron is directed to hepatocytes which store increased iron (shown in dark grey). RES iron is also increased by greater erythrophagocytosis of transfused RBCs and increased hepcidin synthesis in hepatocytes (less hypoxia and lower erythropoietic rate). Tf saturation increases relative to nontransfused SCD, but rarely to the levels seen in TM and typically without NTBI formation. Continued hemolysis of remaining sickle RBCs continues to route heme iron away from the erythrophagocytosis- transferrin circuit to hepatocyte and kidney so that Tf saturation does not increase as much as in nonhemolytic conditions despite reduced erythroid uptake. Iron balance with transfusion regimes in SCD and chelation doses required to balance iron loading Transfusion modality Iron accumulation mg/kg/d DFO dose to balance input DFX dose to balance input Simple transfusion Target 30% HbS 0. The loading rate with simple transfusion is higher when the target %HbS is lower (Kim et al12). Automated exchange can be adjusted to achieve minimal iron loading. Iron excretion as a function of dose has been calculated for DFO and DFX chelation therapy (Cohen et al11)sothatappropriatedosestomaintainironbalancecanbeshown. Labile plasma iron is shown across disease states in patients groups with broadly similar SF values. It can be seen that LPI is lower in SCD than other transfusion-dependent anaemias. Venous access can be oxidative stress such as plasma malondialdehyde and nitrate were limiting because 2 good peripheral veins are required to achieve higher in iron overloaded than nonloaded SCD patients and acceptable ﬂow rates; otherwise, repeated femoral access may be correlated with SF. Vortex ports are another signiﬁcantly associated with impairment of the glutathione sys- option, but carry a risk of infection or thrombosis. Lower ﬂow rates with control subjects and correlated with plasma iron. In mouse models of SCD and TM, heme removed and 3 replaced with the difference in volume made up with promoted oxidative stress but hemopexin decreased it. Hemopexin saline, a net Hb increase of 1 g/dL occurs due to the greater appeared to act by decreasing heme-iron loading in the cardiovascu- hematocrit of the transfused than the venesected blood. Net iron lar system, thereby decreasing oxidative stress in the endothelium loading estimated from ferritin increments is 40% of that with decreased induction of adhesion molecules, and was associated obtained with simple top-up transfusion of one unit. Extrahepatic iron distribution is relatively uncommon in SCD Iron overload was present in approximately one-third of 141 adult compared with TM. Iron derived from transfused RBCs initially SCD patients at post mortem (mean age, 36 y),13 and 7% of deaths accumulates in macrophages (capacity of the reticuloendothelial were judged to be related to iron overload. This was conﬁrmed in a study of cellular iron distribution by overload (cirrhosis: 8, heart failure: 2). Endocrine disturbances through mechanisms involving redox cycling of unliganded iron in attributable to iron overload are rare in SCD22 but MRI data are plasma non-transferrin-bound iron (NTBI) or within cells (labile scarce. In TM, the anterior pituitary is the ﬁrst part of the endocrine iron pools), generating hydroxyl radicals and oxidative damage to system to be affected by iron overload. In a preliminary study23 MRI organelles, cell membranes, and DNA (for detailed review, see evidence of pituitary iron was compared between controls and Kwiatkowski and Porter9). The proinﬂammatory state in SCD in patients with SCD, Diamond Blackfan anemia, and TM. Although, iron overload has also been described and contrasted with that of as expected, pituitary iron was highest in Diamond Blackfan anemia TM. Gamma-tocopherol, a nitric oxide–selective An inverse correlation between pituitary volume and estimated antioxidant, was increased 36% in SCD relative to TM. Markers of pituitary iron and thus its endocrine reserve was also found. Hematology 2013 449 Therefore, MRI may in principle identify early pituitary iron IL-6 and IL-10 levels is present in SCD,29 elevated hepcidin deposition in SCD before clinical manifestations are apparent. Conversely, the signal was highest in nontransfused patients with high lactate high levels of IE in TM syndromes may decrease hepcidin dehydrogenase levels, lacked correlation with LIC, and was higher synthesis. However, we have found that although plasma hepcidin than in TM patients. This suggests that kidney R2* may be a levels increase with SF in transfused patients, when adjusted for SF, biomarker for chronic hemolysis-mediated vascular complications they do not differ from non-transfusion-dependent TM or TM, and in SCD. Other investigators have also found low hepcidin in SCD compared Hepatic consequences of transfusional iron overload with healthy controls (Figure 1A). These ﬁndings make raised in SCD hepcidin synthesis an unlikely mechanism for low NTBI in SCD. Other mechanisms involving hepcidin, such as autocrine hepcidin Studies of liver biopsies in SCD have linked transfusional iron load synthesis30 or variability in ferroportin sensitivity to hepcidin,31 are with LIC, ﬁbrosis, and cirrhosis.
Fenoterol compared with terbutaline: Demographic and study characteristics of studies with effectiveness outcomes Mean age in Other medications Author Study Total years % permitted during Year duration Intervention N (SD) Female the study Quality Funding Adult asthma Anderson Single Fenoterol 0 generic 75 mg doxepin with mastercard. Quick-relief medications for asthma Page 53 of 113 Final Report Update 1 Drug Effectiveness Review Project Table 13 purchase generic doxepin on-line. Fenoterol compared with terbutaline: Effectiveness outcomes Baseline Follow-up Mean Mean (SD) (SD) Outcome or or Author Outcome (unit) at Total No Total No Year Category time point Intervention N (%) N (%) Comments Adult asthma Anderson Symptoms Breathing Fenoterol 0 purchase 25mg doxepin amex. Quick-relief medications for asthma Page 54 of 113 Final Report Update 1 Drug Effectiveness Review Project a Table 14. Withdrawal rates for included studies Withdrawals Total due to Author Study withdrawals adverse Population Year duration Intervention N (%) events (%) Albuterol compared with fenoterol Adult asthma Newhouse Multidose, 1 Albuterol 100 µg 129 0 0 1996 day Fenoterol 200 µg 128 0. Quick-relief medications for asthma Page 57 of 113 Final Report Update 1 Drug Effectiveness Review Project REFERENCES 1. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Expert Panel Report: Guidelines for the diagnosis and management of asthma. Contemporary management of chronic obstructive pulmonary disease: scientific review. Twelve-week efficacy and safety comparison of Airomir (salbutamol sulphate in CFC-free system) and CFC salbutamol. HFA formulation of fenoterol and ipratropium MDI is as safe and effective as the CFC formulation for long-term treatment of children with asthma [abstract]. Comparable bronchodilation with hydrofluoroalkane-134a (HFA) albuterol and chlorofluorocarbons-11/12 (CFC) albuterol in children with asthma. The Journal of asthma : official journal of the Association for the Care of Asthma. Anticholinergic therapy for chronic asthma in children over two years of age. Combined inhaled anticholinergics and beta -agonists for2 initial treatment of acute asthma in children. Thomson Micromedex delivers evidence-based clinical knowledge solutions that empower professionals to make better decisions faster. Anticholinergic agents for chronic asthma in adults. Breath-actuated inhalers: comparison of terbutaline Turbohaler with salbutamol Rotahaler. Comparative investigations on pirbuterol, salbutamol and placebo aerosols in bronchial asthma. Pirbuterol aerosol versus salbutamol and placebo aerosols in bronchial asthma. A comparison of salbutamol and terbutaline aerosols in bronchial asthma. Comparison of the efficacy of formoterol and salmeterol in patients with reversible obstructive airway disease: a multicenter, randomized, open-label trial. Quick-relief medications for asthma Page 58 of 113 Final Report Update 1 Drug Effectiveness Review Project 18. Gawchik SM, Saccar CL, Noonan M, Reasner DS, DeGraw SS. The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients. Gioulekas D, Papakosta D, Vordoyianni P, Baloti H, Vamvalis C. A comparison of the clinical efficacy and patient acceptability of terbutaline Turbuhaler and salbutamol Rotahaler, in adult patients with asthma. Effects of prior treatment with salmeterol and formoterol on airway and systemic beta 2 responses to fenoterol. Treatment of nocturnal asthma with fenoterol (Berotec). Lindsay DA, Russell NL, Thompson JE, Warnock TH, Shellshear ID, Buchanan PR. A multicentre comparison of the efficacy of terbutaline Turbuhaler and salbutamol pressurized metered dose inhaler in hot, humid regions. A comparison of inhaled powders of fenoterol and salbutamol in asthma. Inhalation of fenoterol (Berotec) by asthmatic children: A clinical comparison with salbutamol, orciprenaline and isoprenaline. A comparative study of the inhaled dry powders of salbutamol and fenoterol and their delivery systems. Risk of severe life threatening asthma and beta agonist type: an example of confounding by severity. Double-blind trial with standard doses of fenoterol and salbutamol in asthmatic children. The use of fenoterol powder for the treatment of children with asthma.
Island structure con- ﬁnes selection within hosts to the limited genetic variation that enters with initial infection or arises de novo by mutation order doxepin visa. Islandstructurealso enhances stochastic ﬂuctuations because each host receives only a very small sample of parasite diversity purchase doxepin 25 mg with amex. As the number of genotypes coloniz- ing a host rises purchase doxepin with paypal, selection becomes more powerful and stochastic per- turbations decline in importance. Rouzine and Coﬃn (1999) apply the balance between selectionandstochastic perturbation to the observed patterns of genetic variability in HIV. The ﬁnal section takes up promising lines of study for future research. It is useful to distinguish diﬀerent kinds of genetic associations. LINKAGE DISEQUILIBRIUM BETWEEN ANTIGENIC LOCI Statistical association between alleles at diﬀerent loci is called link- age disequilibrium. Linkage disequilibrium arises when alleles occur to- gether in individuals (or haploid gametes) more or less frequently than expected by chance. Immune pressure by hosts could potentially create linkage disequilib- rium between antigenic loci of the parasite (Gupta et al. Suppose that the parasite genotype A/B infects many hosts during an epidemic, leaving most hosts recovered and immune to any parasite genotype with either A or B. Thengenotypes A/B and A /B will be selected against, but A /B can spread. Thus, host immunity favors strong linkage dise- quilibrium in the parasites, dominated by the two strains A/B and A /B. GENOME-WIDE LINKAGE DISEQUILIBRIUM Linkage disequilibrium over the entire genome arises when there is some barrier to genetic mixing between lineages, such as spatial isola- tion or lack of sex and recombination. When lineages do not mix, then 150 CHAPTER 10 the particular amino acid substitutions in each lineage become locked together by their common pattern of inheritance. Genome-wide linkage disequilibrium has been observed in some parasites but not in others (Maynard Smith et al. Immune pressure can create associations between diﬀerent antigenic loci of the parasite. But if the parasite mixes its genome by recombina- tion, nonantigenic loci will often remain in linkage equilibrium and will not be separated into discrete strains. Consider, for example, a third, nonantigenic locus with the allele C causing severe disease symptoms and the equally frequent allele C causing mild symptoms. Strong host immune pressure could potentially separate the antigenic loci into discrete strains, A/B and A /B. Butifrecombination occurs, the nonantigenic locus will be randomly associated with each strain, for example, A/B/C and A/B/C will occur equally frequently. The alleles C and C will also be distributedequally within the A /B antigenicstrain. Immunity by itself does not organize the entire parasite genome into discrete, nonoverlapping strains(Hastings and Wedgwood-Oppenheim 1997). The distinction between antigenic and genome-wide linkage is impor- tant for medical applications. If genome-wide linkage occurs, then each strain deﬁnes a separate biological unit with its own immune interac- tions, virulence characteristics, and response to drugs (Tibayrenc et al. Strains can be typed, followed epidemiologically, and treated based on information from a small number of identifying markers of the genome. ASSOCIATION BETWEEN COINFECTING PARASITES Several parasite genotypes may infect a single host. A recent survey of the literature found nonrandom associations between parasite geno- typeswithinhosts (Lord et al. For sexual parasites, nonrandom associations within hosts often aﬀect mating patterns. Mating typically occurs between the parasites within a host or between parasites in a vector that were recently derived from one or a few hosts. Nonrandom mating alters heterozygosity at individual loci and the opportunities for recombination between loci. Host immunity may inﬂuence the distribution of strains within hosts. Theirdata suggest that the two variants mutually interfere with T cell attack against the parasite, so both variants do betterinthehost when they are together. In general, the immunological proﬁle of each host constrains the range of parasite variants that may coinfect that host. EFFECTIVE POPULATION SIZE The number of adult genotypes sampled to produce the progeny gen- eration inﬂuences the eﬀective size of the population (Wright 1969; Crow and Kimura 1970; Li 1976; Hartl and Clark 1997; Hedrick 2000). Population size aﬀects many statistical properties of genetic structure. For example, suppose a particular parasite genotype sweeps through ahost population, causing a widespread epidemic.