By R. Dolok. Northeastern University. 2019.

Based on the results of this trial generic biaxin 500 mg, the Joint National Beta blockers Page 20 of 122 Final Report Update 4 Drug Effectiveness Review Project Committee on the Prevention cheap 250 mg biaxin fast delivery, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7) recommends a diuretic as the first-line treatment for most patients who have Stage 1 18 hypertension without compelling indications. Quality of life There was no definitive evidence that 1 beta blocker yields a better quality of life than another 19 for patients who have hypertension. Eight trials directly compared different beta blockers on changes of quality of life-associated measures. We excluded 2 trials of atenolol compared with 7, 20 propranolol based on poor-quality ratings. The methods described in these publications were insufficient to rule out the possibilities that results were biased by inadequate randomization procedures (methods weren’t described and baseline characteristics weren’t reported) and/or by mishandling of missing data (attrition reasons not described and proportion of patients included in analyses not reported). Table 4 below summarizes the results of the fair-quality trials. The strongest evidence of any differences between beta blockers came from a 4 week trial of captopril, enalapril, propranolol, and atenolol that used a larger sample size (N=360) and 8 a parallel design. This was the only trial that is clearly industry-funded. Patients were all men that were “at least 21 years of age, employed or retired, educated at high-school level or equivalent, and married or living with a significant other. It remains unclear, however, as to whether these short-term results in men can be generalized to a broader population over a longer period of time. The strength of the evidence from the remaining trials was limited by smaller sample 5, 19, 21-23 sizes and, in the crossover trials, results that were averaged across treatment periods. Improvement in self-rated sexual interest (Minor Symptom Evaluation profile) was greater for 5 atenolol than metoprolol CR in 1 trial of 60 patients (mean age 58 years; 43. Two trials of metoprolol succinate compared to nebivolol examined quality of life measures. One trial was conducted in Germany and compared nebivolol 5 mg to metoprolol succinate 95 mg. After 12 weeks of treatment, 48 men (ages 40 to 55) with newly diagnosed hypertension experienced decreased sexual function on metoprolol 95 mg, but not nebivolol 5 23 mg. However, the article provides insufficient detail to determine how the metoprolol succinate 95 mg product compares to the metoprolol succinate product available in the United States and Canada. In another trial, after 6 weeks of treatment of 46 adults with mild hypertension, sleep quality, as measured by scores on the Pittsburgh Sleep Quality Index, was improved by treatment 19 with nebivolol 5 mg, but declined following treatment with metoprolol CR 100 mg. Beta blockers Page 21 of 122 Final Report Update 4 Drug Effectiveness Review Project Table 4. Quality-of-life outcomes in head-to-head trials of hypertensives Comparison Trial Design Duration Washout (quality) Sample size (weeks) (weeks) Results Atenolol superior to propranolol on some Atenolol vs. Steiner Psychologic General Well-Being, SCL-90-R, and 8 propranolol 1990 4 NA Life Satisfaction indices and no differences on Parallel (Fair) Insomnia Symptom Questionnaire or Sexual N=360 Function Questionnaire Atenolol vs. Atenolol superior to propranolol on 1 Minor Walle 5 metoprolol CR Symptom Evaluation item; no differences in all 1994 6 NR Crossover other Minor Symptom Evaluation and (Fair) N=16 Psychologic General Well-Being scores Buhler Atenolol vs. Nebivolol (32% poor sleepers) compared with 2008 Metoprolol ER 6 NR metoprolol (76% poor sleepers) (P=0. N=48 Abbreviations: NA, not applicable; NR, not reported; PSQI, Pittsburgh Sleep Quality Index. Two placebo-controlled trials reported the effect of long-term beta blocker therapy on quality of life in otherwise healthy patients who have hypertension (Evidence Tables 1 and 2). After 6 months, atenolol and placebo were similar on several dimensions from the Life Satisfaction Scale, the Physical Complaints Inventory, and the Symptoms Checklist, including summary (“total physical problems”, “overall psychological functioning”, “overall life satisfaction”), distress (“sexual physical problems”, “depression”, “anxiety”, “sleep disturbances”, “fatigue”), and well-being (“satisfaction with physical health”, 27 “sexual satisfaction”). In the second trial, there were no differences between propranolol and placebo in cognitive or psychological measures after 1 year of treatment. Beta blockers Page 22 of 122 Final Report Update 4 Drug Effectiveness Review Project Key Question 1b. For adult patients with angina, do beta blockers differ in efficacy or effectiveness? Summary There were no differences in exercise tolerance or attack frequency in head-to-head trials of carvedilol compared with metoprolol, pindolol compared with propranolol, betaxolol compared with propranolol, and betaxolol compared with metoprolol tartrate in patients with chronic stable angina. Atenolol and bisoprolol were equivalent in angina patients with chronic obstructive pulmonary disease. Atenolol and labetalol (when combined with chlorthalidone) were equivalent in angina patients with hypertension. Beta blockers that had intrinsic sympathomimetic activity reduced the resting heart rate less than other beta blockers, a potential disadvantage in patients suffering from angina pectoris. For this reason, experts recommend against using beta blockers with intrinsic sympathomimetic activity in patients with angina.

Similar approaches using a Sleeping hemoglobin F (HgF) production and reduce hemoglobin S (HgS) Beauty transposon (nonviral) approach via a nucleofection gene production cheap biaxin 500mg on line. In the second and third trimesters of fetal sickling discount biaxin 500 mg mastercard. After birth, the opposite occurs and -globin sickle mice with prior expression of human -globin and S-globin. A summary of gene KLF-1, MYB, SOX6) highly sensitive to DNase 1 in erythroid cells therapy/transduction approaches to induce -globins with antisick- 40-60 kb upstream from the -globin gene, respectively (Figure ling properties is illustrated in Figure 3. Human -globin gene locus on chromosome 11 showing the ontology of expression of the embryonic, fetal, and adult globin genes controlled by locus control regions. In adult life, the transcription of -globin is highly repressed. Some of the major transcription factors involved in the repression of -globin are highlighted. Reprinted with permission from Chandrakasan and Malik, 2014. Lastly, the Orkin group demonstrated that BCL11A is a major repressor of human -globin expression and that Currently, St Jude’s Research Hospital has an open clinical trial silencing of BCL11A in humanized sickling mice significantly entitled “Retroviral Vector Mediated Globin Gene Transfer to enhances HgF production and SCD-related hematological and Correct Sickle Cell Anemia or Thalassemia” (www. CD34 cells purified from the BM of research participants with a sickle cell syndrome or a thalassemia Most recently, the technology to develop iPSCs from mature syndrome will be transduced with retroviral vectors containing somatic cells has allowed advanced gene editing approaches using -globin coding sequences under the control of the -globin gene site directed endonucleases, such as zinc finger nucleases, transcrip- promoter and including various regulatory elements chosen to tion activator-like effector nucleases, and clustered regulatory enhance gene expression and to insulate regulatory elements from interspaced short palindromic repeat endonucleases, to induce cellular genes at or near the integration sites. The efficiency of gene double-stranded DNA breaks and after nonhomologous end joining transfer and the function of the globin transgene will be evaluated in or homology-directed repair/homologous reconstitution gene correc- erythroid cells derived from transduced progenitors and from the Figure 3. The genome of both wild-type murine MLV (A) and the HIV-1 virus and the gene therapy vectors derived from them (B). The initial retroviral vectors had full-length long terminal repeats (LTRs) with intact U3 region (which carries the viral enhancer and promoter). With the current generation of LVs, the U3 region of the 3 LTR is deleted and in the 5 LTR, it is replaced by a CMV promoter in the 5 LTR. The CMV promoter is only used in packaging the vector and is not transmitted to host cells. Reprinted with permission from Chandrakasan and Malik, 2014. This study will evaluate whether a vector can be designed to achieve both a potentially therapeutic efficiency of gene transfer into repopulating cells and a potentially therapeutic level of globin gene expression in maturing erythroid cells. A second clinical trial is about to open at the time of this writing entitled “A Phase 1 Study Evaluating Gene Therapy by Transplantation of Autologous CD34 Stem Cells Transduced Ex Vivo With the LentiGlobin BB305 Lentiviral Vector in Subjects With Severe Sickle Cell Disease. The study will evaluate the safety and efficacy of the LentiGlobin BB305 drug product consisting of autologous CD34 HSCs transduced with LentiGlobin BB305 LV vector encoding the human beta A-T87Q-globin gene (www. Summary MAC with HLA MSD allo-HSCT is the only known curative therapy in patients with SCD. More novel approaches are being investigated, including RIC and the use of alternative allogeneic donors (MUDs, UCBT, haploidentical) and autologous gene correc- tion/replacement stem cell therapies. Prospects are bright for new stem cell approaches for patients with SCD and we are able to offer a greater number of patients a potential cure from this chronic and debilitating condition. Acknowledgments This work was supported in part by grants from the FDA (Grant 5R01FD004090) and the Pediatric Cancer Research Foundation. The authors thank Yaya Chu and Sanghoon Lee for their significant contribution to the production of Figure 4A-D and Erin Morris for her editorial assistance in the production of this manuscript. Cairo, MD, Chief, Pediatric Hematology, Oncology and Stem Cell Transplantation, Director, Children and Adolescent Cancer and Blood Diseases Center, Medical and Scientific Director, Cellular and Tissue Engineering Laboratory, Associate Chairman, Department of Pediatrics, Professor of Pediatrics, Medicine, Pathol- ogy, Microbiology & Immunology and Cell Biology & Anatomy, Maria Fareri Children’s Hospital at Westchester Medical Center, New York Medical College, 40 Sunshine Cottage Rd, Skyline Office, 1N-D12 Valhalla, NY 10595; Phone: 914-594-2150; Fax: 914-594-2151; e-mail: mitchell_cairo@nymc. Bone marrow transplanta- effector nucleases (TALENs)-mediated human beta-globin (HBB) gene tion for sickle cell disease. Matched-related donor palindromic repeats (CRISPR)/CRISPR-associated (Cas)-mediated transplantation for sickle cell disease: report from the Center for human -globin (HBB) gene correction in SCD. Long-term results of related Hematology 2014 473 myeloablative stem-cell transplantation to cure sickle cell disease. Purified T-depleted, CD34 tation from an HLA-identical sibling. Haematopoietic stem cell transplanta- cal mother to child with thalassemia. Pulmonary, gonadal, and tion for patients with high-risk sickle cell disease (SCD) (IND 14359). Impact of bone marrow state of the field and the future. Multicenter investigation of bone marrow transplantation for sickle cell 26. Grosveld F, van Assendelft GB, Greaves DR, Kollias G. Stable long-term independent, high-level expression of the human beta-globin gene in donor engraftment following reduced-intensity hematopoietic cell trans- transgenic mice.

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ECG as appropriate • Serous borderline ovarian tumors are in 25–50% bilateral buy 250mg biaxin overnight delivery, and 25–30% of the patients may have Culdocentesis and culdotomy (see Chapters 12 and 18) in some extra-ovarian disease so staging is appro- case of free fluid in Douglas’ pouch 8 priate purchase biaxin 250mg line. Frozen section diagnosis of a low malig- Cystoscopy and rectoscopy if available nant potential tumor of the ovary is changed to CT scan or MRI as appropriate and if available in the a final diagnosis of invasive cancer in approxi- hospital mately 10% of cases. Serous borderline tumors may have (invasive or non-invasive) implants. Explorative laparotomy Most patients present with an asymptomatic pel- vic/abdominal mass. On ultrasound the tumor is mostly multilocular with papillary formations but without ascites, but a non-suspicious cyst does Table 8 Key points in diagnosis and treatment of a not exclude borderline disease. Ca-125 may be swollen abdomen/abdominal mass (slightly) elevated. Look for signs of shock: pallor, low blood pressure and Therapy Surgical staging without pelvic and para- low volume rapid pulse aortal lymph node dissection as this does not influ- Lower abdominal/pelvic tenderness, rigidity, rebound or ence the prognosis9: obtain free fluid or wash the guarding and any mass arising from the pelvis abdomen for cytology, systematically examine Inspect the vulva for any bleeding the whole abdomen (see Chapter 28) and take a biopsy of any suspicious lesion, take biopsies of the Vaginal examination as appropriate +/- swabs peritoneal surface of Douglas’ pouch, the bladder Per rectal examination as appropriate peritoneum, the paracolic gutters and the right dia- phragm. Remove the omentum, the uterus, both Always a pregnancy test in any woman of reproductive age tubes and ovaries (see Chapter 19 for method). Consider a diag- patients who wish to spare their fertility a unilateral nostic peritoneal lavage in case of free fluid either by oophorectomy can be performed and the uterus culdocentesis or abdominal tapping depending on the and the healthy adnexa will not be removed. The most reliable prognostic indi- of dilatation of the cervical stenosis but always in cator for advanced stage tumors is the type of endometrial sampling (see Chapters 20 and 29) and peritoneal implant. Survival of patients with non- cervical examination to exclude malignancy. In cases invasive peritoneal implants is 95%, compared with of pyometra, the pus is most commonly sterile, so 66% for invasive implants, and lymph node involvement was associated with a 98% survival9. It is more important to produce There is no place for adjuvant chemotherapy in a specimen for histology. Treatment of hematometra/pyometra is a care- ful D&C under anesthesia and if possible under Benign ovarian cysts and tumors ultrasound guidance. Persistent or big ovarian cysts Borderline ovarian tumors Persistent or big ovarian cysts with sonographically These are ovarian tumors with low malignant suspicious features (see above) should be assessed by potential that occur mainly in premenopausal surgery (laparotomy or if available laparoscopy 108 Abdominal Masses in Gynecology Table 9 Common gynecological conditions associated with abdominal masses Gynecological condition Common symptoms associated with pelvic mass Uterine fibroids Reproductive age, abnormal uterine bleeding, secondary dysmenorrhea, frequent voiding, constipation, chronic pelvic or back pain, recurrent mis- carriage, infertility Advanced uterine cancer or sarcoma Postmenopausal bleeding, pressure symptoms, pelvic pain, rapid growth of uterine mass in sarcoma Endometriosis Reproductive age, chronic pelvic pain, secondary dysmenorrhea, dyspareunia, infertility Tubo-ovarian abscess, pyosalpinx, Reproductive age, chronic pelvic pain with aggravation, dyspareunia, often hydrosalpinx intermenstrual bleeding, spotting, abnormal vaginal discharge, infertility. A hydrosalpinx is most often symptomless Benign ovarian cysts or tumors Reproductive age, often symptomless, acute or chronic pelvic pain, pressure symptoms, sometimes irregular cycles, spotting Ovarian cancer Peak age postmenopausal, increased abdominal circumference, sometimes dyspnea, postmenopausal bleeding, pressure symptoms, obstipation or ileus by a skilled surgeon). Note however, that you mass you should not attempt this surgery unless you should not attempt doing a mini-laparotomy or are very experienced and able to repair a bowel or unskilled laparoscopy on an ovarian tumor with bladder lesion. If you are able to identify and suspicious sonographic features. If it ruptures intra- mobilize (do this bluntly with your fingers! Tubo-ovarian masses associated with pelvic inflammatory disease Simple ovarian cysts Tubo-ovarian masses associated with pelvic inflam- These are very common in women of reproductive matory disease (PID) are difficult to assess. Reconstructive tubal sur- logical, watchful waiting for two to six cycles is gery to restore tubal patency exists but should be appropriate in an asymptomatic simple cyst of carried out by experienced surgeons. If you try to <5cm diameter in a premenopausal woman. Re- just re-open the hydrosalpinx there is a significant scan after 3 and 6 months. If still persistent after increase in the risk of ectopic pregnancy in that 6 months, surgery may be appropriate. In cases of pelvic abscess do a culdocentesis common practice in many settings to treat simple (see Chapter 12) first and if pus is drained do a cul- ovarian cysts with oral contraceptives but a dotomy as described in Chapter 18. If the tubo- Cochrane review on this subject showed no benefit ovarian abscess doesn’t reach the pouch of Douglas of this treatment over watchful waiting10 (level of you will have to do a laparotomy. If all organs are included in the patients see Chapter 24. The risk of malignancy is low in this • Identify the adnexa with the mass and assess for age group (1 : 1000)11. It is always important in this potential malignancy. If there is free fluid in the age group to consider fertility preservation in your pouch of Douglas and you have the possibility treatment. If <5cm, re-scan after 3 and 6 months; of cytology, take a specimen with a small syringe. It is important to Assess the mass if there is any rupture, outside discuss the implications of regular visits to the growth or infiltration of other structures. But as there is still a chance of malig- symptomatic at any visit you may remove it. Aspi- nancy take utmost care to remove the adnexa ration of the content of a cyst abdominally or vagi- with the mass intact. Adnexal around the round ligament with a blunt forceps removal will be by laparotomy in most settings; if and incise it and widen this opening carefully laparoscopy is available and you are experienced in towards the pelvic wall parallel to the infundi- this type of surgery, a non-suspicious simple cyst or bulopelvic ligament. If the cyst is unilocular and shows no signs of the ureter which is usually in the medial part of malignancy in ultrasound you might consider a the space you created and runs from the pelvic mini-laparotomy.

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The target dose of carvedilol was 25 mg twice a day and the target for metoprolol tartrate was 50 mg twice a day order biaxin 500mg free shipping. Beta blockers Page 41 of 122 Final Report Update 4 Drug Effectiveness Review Project When COMET was designed generic biaxin 500mg free shipping, extended-release metoprolol was not yet available, and immediate-release metoprolol was a logical comparator because in the MDC trial metoprolol tartrate was clearly effective, even though it did not change mortality. Specifically, metoprolol tartrate improved ejection fraction, left ventricular end diastolic pressure, and exercise time and prevented clinical deterioration, reducing the need for transplantation by almost 90% during the 94 followup period. Mortality In COMET, after a mean followup of 58 months (nearly 5 years), the intention-to-treat analysis showed an all-cause mortality reduction in favor of carvedilol (34% compared with 40%; number needed to treat, 18; P<0. The annual mortality rate was 10% for metoprolol tartrate and 8. For comparison, the rates were for metoprolol succinate in MERIT-HF (7. There was no difference between carvedilol and metoprolol in the combined endpoint of deaths plus all-cause admissions (74% compared with 76%). COMET demonstrates unequivocally that carvedilol 25 mg twice a day was better than immediate-release metoprolol (metoprolol tartrate) twice a day. There is disagreement, however, about the relevance of the result, because immediate-release metoprolol had not been shown to reduce mortality in previous trials. Several years ago, after metoprolol tartrate failed to reduce mortality in the Metoprolol in Dilated Cardiomyopathy (MDC) trial, it was hypothesized that the patients who received it were subjected to daily variations in the degree of beta blockade. In COMET, the mean dose of metoprolol tartrate was less than that used in the MDC trial (85 mg daily compared with 108 mg daily), and the mean decrease in heart rate was also less (11. Subsequently, extended-release metoprolol (metoprolol succinate) was proven to reduce mortality in heart failure patients in the MERIT-HF trial. In MERIT-HF, the mean dose of metoprolol succinate was 159 mg daily and the mean reduction in heart rate was 14 beats per minute. Evidence on numerous secondary outcomes from the 108, 109, 110 COMET trial have been published. Carvedilol was superior to immediate-release metoprolol in reducing rates of cardiovascular death, sudden death, stroke, cardiovascular events, and unstable angina, and similar to immediate-release metoprolol in reducing death due to circulatory failure and other cardiovascular deaths, as well as in reducing days lost due to 108, 109 impaired well being. Greater reductions in rates of first hospitalization due to potential complication of heart failure treatment were more associated with immediate-release metoprolol than with carvedilol. Both interventions had similar effects on rates of overall hospitalization and cause-specific 108, 109 hospitalizations, with 1 exception. Rates of non-cardiovascular death, worsening heart failure, change in New York Heart Association classification, and medication withdrawal were 108 similar for carvedilol and immediate release metoprolol. With regard to combined endpoints, carvedilol was superior in reducing rates of fatal or nonfatal myocardial infarction and the combination of cardiovascular death, heart transplantation, hospitalization for nonfatal acute myocardial infarction, or worsening heart failure and was similar to immediate-release metoprolol in reducing the combined rate of all- 108 cause mortality and cardiovascular hospitalizations. Another combined endpoint of days of life Beta blockers Page 42 of 122 Final Report Update 4 Drug Effectiveness Review Project lost due to death, hospitalization, impaired well-being, or need to increase diuretic use (deemed the ‘patient journey’) found carvedilol to be superior to metoprolol over 4 years when compared 109 to baseline composite scores (P=0. It is important to note however, that this combined endpoint considered all factors to be equal; days lost due to death were considered equivalent to days lost due to hospitalization. In the older trials, there was a nonsignificant trend favoring carvedilol over immediate- release metoprolol. Carvedilol and immediate release metoprolol (124+/−55 mg daily) had similar effects on quality of life, but metoprolol improved exercise capacity more. There were no differences between the carvedilol and metoprolol groups in quality of life. One trial of 70 patients with heart failure, a left ventricular ejection fraction of 40% or lower, and a New York Heart Association functional class of II or III, compared treatment with mean doses of carvedilol 44 mg and a lower than recommended target dose of nebivolol (4. Compared with baseline, carvedilol and nebivolol demonstrated slight improvements in New York Heart Association 111 functional class and the 6-minute walk test. For adult patients with atrial arrhythmia, do beta blockers differ in efficacy or effectiveness? Several beta blockers have been used to reduce the heart rate in patients with atrial tachyarrhythmias and to prevent relapse into atrial fibrillation or flutter. A recent good-quality systematic review examined 12 studies of rate control in patients with chronic atrial 112 fibrillation. Atenolol, nadolol, and pindolol were effective in controlling the ventricular rate, while labetalol was no more efficacious than placebo. We found 1 head-to-head trial comparing bisoprolol 10 mg and carvedilol 50 mg in 113 patients subjected to cardioversion of persistent atrial fibrillation (> 7 days). This fair-quality, 12-month trial enrolled 90 patients (mean age, 65. Similar proportions of patients relapsed into atrial fibrillation during follow-up in the bisoprolol and carvedilol groups (53. Two placebo-controlled trials evaluated beta blockers in patients with persistent atrial 114-116 fibrillation. One placebo-controlled trial found that metoprolol CR/XL 100 to 200 mg was effective in preventing relapse of atrial fibrillation/flutter after cardioversion (Evidence Table 114, 115 14). This fair-quality trial was conducted in Germany and enrolled 433 patients after cardioversion of persistent atrial fibrillation that were 70% male, with a mean age of 60. Over 6 months, atrial fibrillation or flutter relapse rates were significantly lower in patients taking metoprolol CR/XL (48.