By Q. Gunnar. New Mexico Highlands University. 2019.
PLoS One 2013;8:e54452 Ernst D purchase 75mg sildenafil amex, Pischke S order 50 mg sildenafil free shipping, Greer M sildenafil 75mg free shipping, Wedemeyer H, Stoll M. No increased incidence for GB-virus C infection in a cohort of HIV-positive lymphoma patients. Int J Cancer 2011;128:3013 Ernst D, Greer M, Akmatova R, et al. Impact of GB virus C viraemia on clinical outcome in HIV-1-infected patients: a 20-year follow-up study. HIV Med 2014;15:245-50 Gutierrez, RA, Dawson GJ, Knigge MF, et al. Seroprevalence of GB virus C and persistence of RNA and antibody. Impact of GB virus type C infection on mother-to-child HIV trans- mission in the Women and Infants Transmission Study Cohort. Beneficial effect of GB virus C co-infection in Human Immunodeficiency Virus type 1-infected individuals. GB virus C/hepatitis G virus infection: a favorable prognostic factor in hiv-infected patients? Synthetic peptides of hepatitis G virus (GBV-C/HGV) in the selection of putative peptide inhibitors of the HIV-1 fusion peptide. Prevalence and clinical significance of GB virus type C/hepatitis G virus coinfection in patients with chronic hepatitis C undergoing antiviral therapy. J Viral Hepat 2011;18:513-7 Jung S, Eichenmuller M, Donhauser N, et al. HIV entry inhibition by the envelope 2 glycoprotein of GB virus C. Kaufman TM, McLinden JH, Xiang J, Engel AM, Stapleton JT. The GBV-C envelope glycoprotein E2 does not inter- act specifically with CD81. No observed effect of GB virus C coinfection in disease progression in a cohort of African woman infected with HIV-1 and HIV-2. Activation of interferon response genes and of plasmacytoid dendritic cells in HIV-1 positive subjects with GB virus C co-infection. Lauck M, Bailey AL, Andersen KG, Goldberg TL, Sabeti PC, O’Connor DH. GB virus C coinfections in west African Ebola patients. Lefrere JJ, Roudot-Thoraval F, Morand-Joubert L, et al. Carriage of GB virus C/hepatitis G virus RNA is associated with a slower immunologic, virologic, and clinical progression of HIV disease in coinfected persons. GB virus type C infection modulates T-cell activation independ- ently of HIV-1 viral load. Mönkemeyer M, Schmidt RE, Wedemeyer H, Tillmann HL, Heiken H. GBV-C coinfection is negatively correlated to Fas expression and Fas-mediated apoptosis in HIV-1 infected patients. GB virus type C interactions with HIV: the role of envelope glycoproteins. J Viral Hepat 2009;16:757-68 Mohr EL, Xiang J, McLinden JH, et al. GB virus type C envelope protein E2 elicits antibodies that react with a cellular antigen on HIV-1 particles and neutralize diverse HIV-1 isolates. Regulation of CC chemokine receptor 5 in hepatitis G virus infec- tion. Human Pegivirus HPgV Infection 473 Nunnari G, Nigro L, Palermo F, et al. Slower progression of HIV-1 infection in persons with GB virus C co-infec- tion correlates with an intact T-helper 1 cytokine profile. Level of double negative T cells, which produce TGF-beta and IL-10, pre- dicts CD8 T-cell activation in primary HIV-1 infection. AIDS 2012; 26:139-148 Rambusch EG, Wedemeyer H, Tillmann HL, Heringlake S, Manns MP. Significance of coinfection with hepatitis G virus for chonic hepatitis C – a review of the literature. GB virus type C infection polarizes T-cell cytokine gene expression toward a Th1 cytokine profile via NS5A protein expression. J Infect Dis 2012;206:69-72 Schwarze-Zander C, Blackard JT, Zheng H, et al. GB virus C (GBV-C) infection in hepatitis C virus (HCV)/HIV- coinfected patients receiving HCV treatment: importance of the GBV-C genotype. GB virus C coinfection in advanced HIV type-1 disease is asso- ciated with low CCR5 and CXCR4 surface expression on CD4(+) T-cells. Expert Rev Anti Infect Ther 2012;10:563-72 Shankar EM, Balakrishnan P, Vignesh R, et al. Current views on the pathophysiology of GB Virus C coinfection with HIV-1 infection. Stapleton JT, Chaloner K, Zhang J, Klinzman D, et al. GBV-C viremia is associated with reduced CD4 expansion in HIV-infected people receiving HAART and interleukin-2 therapy. The GB viruses: a review and proposed classification of GBV-A, GBV-C (HGV), and GBV-D in genus Pegivirus within the family Flaviviridae. J Gen Virol 2011;92:233-46 Stapleton JT, Martinson JA, Klinzman D, Xiang J, Desai SN, Landay A.
OHL is not caused by fungi but by EBV 75 mg sildenafil mastercard, and is an important disease marker for HIV order 100 mg sildenafil mastercard, even if it is harm- less and does not require treatment 75 mg sildenafil amex. Candida esophagitis can also initially be diagnosed clinically. Dysphagia, retrosternal pain and oral candidiasis make the diagnosis very probable. Empiric fluconazole therapy reduces costs (Wilcox 1996). Upper GI endoscopy is only required if com- plaints persist. To distinguish fluconazole-resistant esophageal candidiasis from herpes or CMV esophagitis, samples of lesions should always be taken. In contrast, determination of serum antibodies or antigen is always unnecessary. Treatment With relatively good immune status at first presentation, treatment with topical antimycotics such as nystatin, amphotericin B or miconazole can be attempted. This is more effective and prevents relapses for longer (Pons 1997). According to a recently published trial, shorter treat- ment duration with higher dosages may be an option. In this large randomized study, a single dose of 750 mg of fluconazole was safe, well tolerated, and as effective as the standard 14-day fluconazole therapy (Hamza 2008). If symptoms last for more than a week, a swab should be taken and the daily flu- conazole dose may be increased to 800 mg for the second attempt. Itraconazole should only be used if the second treatment attempt fails and non-albicans strains have been found. It will be effective in approximately two thirds of cases (Saag 1997). Although itraconazole suspension is as effective as fluconazole (Graybill 1998), we do not primarily use it as plasma levels are unreliable and there are problems due to numerous interactions. A new alternative are miconazole mucoadhesive tablets. These tablets adhere to the oral mucosa and provide sustained local release of miconazole over a period of several hours with just one daily application. Miconazole has recently been approved in Europe (Loramyc) and the USA (Oravig™) for the treatment of oropharyngeal candidiasis (Lalla 2011). In a large trial, miconazole was shown to be noninferior to treatment with clotrimazole 10 mg troches 5 times daily for 14 days in HIV+ patients (Vasquez 2010). Trials comparing miconazole with oral fluconazole are lacking. Several new and promising antimycotics have been developed in recent years. However, these should only be used in clear cases of fluconazole resistance. There is insufficient evidence on the superiority of these drugs in the treatment of non- resistant candidiasis (Pienaar 2006). Voriconazole is expected to be as effective as fluconazole, but is possibly not tolerated as well (Ruhnke 1997, Ally 2001). This may be also true for posaconazole (Vasquez 2006). Like amphotericin B, these new azoles should only be used for treatment of multi-azole resistant mycoses. The new antimycotic class of echinocandins has good efficacy, among them drugs such as caspofungin, micafungin or anidulafungin. These drugs showed similar efficacy and tolerability to intravenous fluconazole for treatment of candida esophagitis in randomized studies (Villaneuva 2001, de Wet 2004, Reboli 2007). However, these drugs can only be administered intravenously which restricts their use to azole-resistant candidiasis. Antiretroviral therapy should be initiated when such mycoses occur, particularly with multiresistant strains, as these usually disappear with sufficient immune recon- stitution (Ruhnke 2000). Treatment/prophylaxis of candidiasis (daily doses) Acute therapy Duration: 5–10 days In mild cases Topical e. In a large randomized study, a reduc- tion in oral candidiasis episodes as well as in invasive candidiasis was observed on long-term prophylaxis (Goldman 2005). The hypothesis that long-term prophylaxis will lead to the selection of resistant non-albicans strains (Vazquez 2001) was not confirmed in this study. Azole resistant infections were not seen more frequently in the long-term therapy group. Nonetheless, every immunocompromised patient should be screened for oral thrush at every visit. Chlorhexidine based gels and mouth rinses have a broad antimicrobial activity, with some antifungal properties. A randomized, double-blind, double-dummy, multicenter trial of voricona- zole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. A randomized, double-blind, parallel-group, dose-response study of micafungin compared with fluconazole for the treatment of esophageal candidiasis in HIV-positive patients. Randomized trial of itraconazole oral solution for oropharyngeal candidiasis in HIV/AIDS patients. Single-dose fluconazole versus standard 2-week therapy for oropha- ryngeal candidiasis in HIV-infected patients: a randomized, double-blind, double-dummy trial. Miconazole mucoadhesive tablet for oropharyngeal candidiasis. Itraconazole prophylaxis for fungal infections in patients with advanced HIV infection: randomized, placebo-controlled, double-blind study. Interventions for the prevention and management of oropharyngeal candidia- sis associated with HIV infection in adults and children. Oropharyngeal candidiasis in patients with AIDS: randomized com- parison of fluconazole versus nystatin oral suspensions.
Therefore discount 75 mg sildenafil with visa, interpretation of results for serious viral skin infections should be considered with some caution cheap 75mg sildenafil free shipping. None of the studies reported skin atrophy sildenafil 25 mg, telangiectasia, or adrenal suppression. The extent and severity of striae however, were not described. Detailed Assessment Harms Good-quality long-term studies evaluating serious harms-related events were not found. Most trials generally reported total withdrawal rates and adverse events that emerged during the study duration. Methods for collecting data on harms (such as actively querying patients rather than passively allowing patients to report events) were not explicitly stated, and methods on how adverse events were reported (for example, selective reporting) generally were not detailed. In a few publications, the number of cases of particular viral infections was not reported for each treatment group, making comparisons between topical calcineurin inhibitors difficult. The severity of adverse events was also not predefined or prespecified. Only 3 trials prespecified 34, 37, 50 investigation of application site reactions, local skin infections, and cases of acne. General 16-19, 23, 24, 34, 35, 39, 48, 49, 51, adverse events were collected from 25 vehicle- and active-control trials. Lymphomas No good-quality, long-term, comparative studies assessing serious harms were found. Two short- 58, 59 term nested case-control studies were identified (Evidence Tables 13 and 14). In one study, cases of lymphoma and controls were identified from the PharMetrics database which included 73 United States health plans. Records in this database represented the managed care population. Initially, patients with ICD-9 codes for atopic dermatitis were collected from 1995 to 2005 and 502 283 patients were identified. After excluding patients who had <6 months enrollment in the database, who had an existing diagnosis of lymphoma, cancer, HIV, or AIDS, or a history of immunosuppressive therapy or transplantation, a total of 293 253 patients served as the final cohort for analysis. Of these patients, 75% were enrolled in the database from 2001 (limiting the total duration of exposure to topical calcineurin inhibitors). At the index date (day an ICD-9 code was present for atopic dermatitis), 1. In these patients, 14 and 11 cases of lymphoma were identified for those exposed to topical pimecrolimus and topical tacrolimus. Topical calcineurin inhibitors Page 33 of 74 Final Report Drug Effectiveness Review Project ICD-9 codes were used to identify cases of lymphoma and the cases were reviewed by blinded hematologists. The authors of this nested case-control state that misclassification of events could 58 have easily occurred and thus the results should be considered with caution. Based on these findings, the odds of lymphoma associated with topical pimecrolimus (odds ratio 0. A second study that assessed the risk of nonmelanoma skin cancer (NMSC) in adults with “dermatitis” who used topical calcineurin inhibitors compared with those who did not use these 59 topical agents was rated poor (see Evidence tables 13 and 14). This study was rated poor- quality based on a combination of factors which included: high risk of recall bias which is also the most difficult to control; unclear description of the selection of the sample; no information regarding duration of illness or duration of exposure to topical calcineurin inhibitors; and no explanation on how missing histologic data (used to confirm cases of NMSC) were handled. Skin atrophy, telangiectasia, adrenal suppression, or skin striae None of the included studies reported skin atrophy, telangiectasia, or adrenal suppression. Of the 50 2 long-term active-control trials, only 1 study reported 3 cases of skin striae (0. Striae were identified on legs between 4 and 9 months and remained until the end of the study. The extent and severity of striae were not described. In this trial, the mean percentage of days on which patients needed to apply study medication was 83. The median percentage of days of exposure to study medications was 95. The study did not report baseline disease duration, did not report baseline topical steroid usage (including potency of past topical steroids and duration of use), and did not specify whether all patients were screened for evidence of skin changes prior to study enrollment. Withdrawals Total withdrawal (pooled relative risk 0. However, tacrolimus-treated patients were less likely to withdraw from treatment secondary to lack of efficacy than pimecrolimus-treated patients (pooled rate 2. Indirect meta-analysis of pimecrolimus and tacrolimus vehicle-controlled trials also showed no significant differences for total withdrawal rates (pooled relative risk, 0. The most common reason for withdrawal for vehicle-treated patients was due to lack of efficacy (pooled 16, 17, 22, 23, 25, 26, 36, 39, 42, 45, 52, 53 rates: 28% compared with 6. Of the 4 active-control trials where topical steroids were as effective as or more effective 18, 51 26, 50 than tacrolimus or pimecrolimus, the rates of total withdrawal were numerically less for Topical calcineurin inhibitors Page 34 of 74 Final Report Drug Effectiveness Review Project 50 those randomized to topical steroids (Table 10). One study, however, did not report withdrawal 19, 48, 49 rates for both treatment groups. For the remaining active-control trials where tacrolimus was shown to be more effective than topical steroids, total withdrawal rates were greater for patients on topical steroids (pooled rates: tacrolimus 14% compared with topical steroids 23%). The most common reason was lack of efficacy (pooled rates: tacrolimus 4. Total withdrawal rates for 4 active-control trials Tacro Pime BMV HB MPA TC+HCA 26 Luger 2001 --- 15. Application site reactions Commonly reported adverse events were application site reactions (burning, stinging, pruritus, etc). Head-to-head studies found no significant difference between tacrolimus (0. Across vehicle-controlled trials, significantly more tacrolimus-treated (up to 52%) and pimecrolimus-treated patients (up to 49%) experienced burning, stinging, erythema, or irritation 16, 17, 22-26, 36, 39, 42, 45, 52-55 during treatment compared with up to 35% of vehicle-treated patients.
Triptan compared with placebo: Characteristics and outcomes Author Year Country Allowed other Method of Outcome Age Trial Name medications/ Assessment and Timing of Gender (Quality Score) interventions Assessment Ethnicity Other population characteristics Carpay Acute migraine Primary efficacy n=481 Without aura only=78 cheap sildenafil 75 mg otc. Triptan compared with placebo: Characteristics and outcomes Results Author Year Country Number screened/ Trial Name eligible/ Number withdrawn/ (Quality Score) enrolled lost to fu/analyzed Relief at various times Carpay nr/nr/481 37(8 order sildenafil 100mg on-line. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name Pain Free at various times (% Presence of migraine-associated (Quality Score) patients) symptoms at 2 hours Other efficacy outcomes Carpay SRR100 vs SRR50 vs placebo SRR50 vs SRR100 vs placebo SRR50vs SRR100 vs placebo 2004 30 minutes: 10 buy cheap sildenafil 75 mg online. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name Method of adverse effects (Quality Score) assessment Adverse Effects Reported Carpay Tolerability was assessed by SRR50 vs SRR100 vs placebo 2004 calculating the incidence of (% patients) Europe specific adverse events, defined as any untoward medical Overall drug-related adverse events: Fair quality occurrences, regardless of 10. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name (Quality Score) Comments Carpay 2004 Europe Fair quality *p<0. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name (Quality Score) Study design Eligibility criteria Interventions Diener RCT, DB, Parallel IHS criteria for migraine with or Almotriptan 12. Triptan compared with placebo: Characteristics and outcomes Author Year Country Allowed other Method of Outcome Age Trial Name medications/ Assessment and Timing of Gender (Quality Score) interventions Assessment Ethnicity Other population characteristics Diener Rescue medication, Primary efficacy outcome: Mean age Mean Height (cm) 2005 choosen by the pain relief at 2 hours (years) Alm: 167. Triptan compared with placebo: Characteristics and outcomes Results Author Year Country Number screened/ Trial Name eligible/ Number withdrawn/ (Quality Score) enrolled lost to fu/analyzed Relief at various times Diener 328/245/221 23/NR/198 Pain-reilef at 2 Hours 2005 Alm: 47. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name Pain Free at various times (% Presence of migraine-associated (Quality Score) patients) symptoms at 2 hours Other efficacy outcomes Diener Pain-free at 2 Hours NR Use of rescue medication 2005 Alm: 33. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name Method of adverse effects (Quality Score) assessment Adverse Effects Reported Diener Patient report Treatment-emergent adverse events 2005 Alm: 7. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name (Quality Score) Comments Diener 2005 Germany Diener 2005 Germany (companion paper) Eletripan Steering Committee 2002 Japan Fair quality *p<0. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name (Quality Score) Study design Eligibility criteria Interventions Freitag, 2008 RCT, DB, Multicenter, IHS criteria-migraine with or without Almotriptan 12. Triptan compared with placebo: Characteristics and outcomes Author Year Country Allowed other Method of Outcome Age Trial Name medications/ Assessment and Timing of Gender (Quality Score) interventions Assessment Ethnicity Other population characteristics Freitag, 2008 Rescue medication Functional disability 40. Triptan compared with placebo: Characteristics and outcomes Results Author Year Country Number screened/ Trial Name eligible/ Number withdrawn/ (Quality Score) enrolled lost to fu/analyzed Relief at various times Freitag, 2008 NR/NR/378 NR/NR/315 24 hour QOL (companion to Matew 2007) social function domain p<0. Three pretreatment variables 1) functional level (p=0. Correlation of other pretreatment variables photophobia, phonophobia, nausea and vomiting were NS. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name Pain Free at various times (% Presence of migraine-associated (Quality Score) patients) symptoms at 2 hours Other efficacy outcomes Freitag, 2008 % of patients pain free and performing % patients with normal function and A vs Pla (companion to Matew 2007) normal activities for pooled group no migraine assciated symptoms Functional disability at 2 hours: (Attack 1) compared to patients with normal funtion 54. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name Method of adverse effects (Quality Score) assessment Adverse Effects Reported Freitag, 2008 Patient report A vs Pla: (companion to Matew 2007) % patients reporting AE: 23% vs 23. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name (Quality Score) Comments Freitag, 2008 (companion to Matew 2007) *p<0. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name (Quality Score) Study design Eligibility criteria Interventions Goadsby RCT, DB, Multicenter, IHS criteria-with or without aura for at Almotriptan 12. Avg frequency of 2-6 episodes per month during the last 3 months. History of untreated or unsuccessfully treated migraine headaces > 4 hours duration *p<0. Triptan compared with placebo: Characteristics and outcomes Author Year Country Allowed other Method of Outcome Age Trial Name medications/ Assessment and Timing of Gender (Quality Score) interventions Assessment Ethnicity Other population characteristics Goadsby Rescue medication Primary efficacy endpoint: % 38. Triptan compared with placebo: Characteristics and outcomes Results Author Year Country Number screened/ Trial Name eligible/ Number withdrawn/ (Quality Score) enrolled lost to fu/analyzed Relief at various times Goadsby 491/NR/491 87/NR/404 NR 2008 Multinational *p<0. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name Pain Free at various times (% Presence of migraine-associated (Quality Score) patients) symptoms at 2 hours Other efficacy outcomes Goadsby 1) A 12. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name Method of adverse effects (Quality Score) assessment Adverse Effects Reported Goadsby Patient report 4. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name (Quality Score) Comments Goadsby 2008 Multinational *p<0. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name (Quality Score) Study design Eligibility criteria Interventions Goldstein RCT, DB, Parallel IHS criteria for migraine with or Sumatriptan succinate 2005 Multicenter without aura; report 1 to 8 (sum) 50mg USA migraines/month; migraines are of at least moderate intensity; be Acetaminophen 500mg, able to distinguish migraines from aspirin 500mg, caffeine other headaches 130mg (AAC) Placebo (pla) *p<0. Triptan compared with placebo: Characteristics and outcomes Author Year Country Allowed other Method of Outcome Age Trial Name medications/ Assessment and Timing of Gender (Quality Score) interventions Assessment Ethnicity Other population characteristics Goldstein Rescue medication Efficacy variables recorded Mean age NR 2005 permitted at baseline, 0. Triptan compared with placebo: Characteristics and outcomes Results Author Year Country Number screened/ Trial Name eligible/ Number withdrawn/ (Quality Score) enrolled lost to fu/analyzed Relief at various times Goldstein 188/171/170 0/0/170 Pain-relief (scale 0-4, with 0=no relief and 2005 4=complete relief) USA At 2 Hours: AAC: 2. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name Pain Free at various times (% Presence of migraine-associated (Quality Score) patients) symptoms at 2 hours Other efficacy outcomes Goldstein NR ACC group had significantly Headache Response (baseline 2005 more decrease of phonophobia of moderate/severe pain USA (p<0. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name Method of adverse effects (Quality Score) assessment Adverse Effects Reported Goldstein Patient report Chest tightness: sum group=1 subject 2005 USA Gastrointestinal complaints: AAC: 15 (21/7%) vs sum: 5 (7. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name (Quality Score) Comments Goldstein 2005 USA *p<0. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name (Quality Score) Study design Eligibility criteria Interventions Jelinski RCT, DB, Double- IHS criteria for migraine with or Sumatriptan 50mg (S50) 2006 dummy, placebo without aura; aged 18 to 65 and 100mg (S100) Canada controlled, parallel years, 1 to 6 migraines/month, Multicenter moderate/severe migraine pain Placebo (Pla) Mathew RCT, DB, Parallel IHS criteria for migraine with or Almotriptan 12. Triptan compared with placebo: Characteristics and outcomes Author Year Country Allowed other Method of Outcome Age Trial Name medications/ Assessment and Timing of Gender (Quality Score) interventions Assessment Ethnicity Other population characteristics Jelinski NR Primary efficacy outcome: Pla; S50; S100 Pla; S50; S100 2006 proportion of patients pain- Mean age Migraine History Canada free at 1, 2, 4 and 24 hours (years): 40. Triptan compared with placebo: Characteristics and outcomes Results Author Year Country Number screened/ Trial Name eligible/ Number withdrawn/ (Quality Score) enrolled lost to fu/analyzed Relief at various times Jelinski 429/364/361 NR/NR/361 NR 2006 Canada Mathew NR/NR/378 61/NR/317 Pain-relief at 1 Hour (%) 2007 Alm: 54. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name Pain Free at various times (% Presence of migraine-associated (Quality Score) patients) symptoms at 2 hours Other efficacy outcomes Jelinski Pain-Free at 1 Hour Nausea reported at 2 Hours: NR 2006 S50: 24% Pla: 7% (p<0. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name Method of adverse effects (Quality Score) assessment Adverse Effects Reported Jelinski Patient report S100: paraesthesias, chest symptoms, 2006 and throat contstriction reported by 3% Canada of subjects Mathew Patient report Somnolence 2007 Alm: 1. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name (Quality Score) Comments Jelinski 2006 Canada Mathew 2007 USA *p<0. Triptan compared with placebo: Characteristics and outcomes Author Year Country Trial Name (Quality Score) Study design Eligibility criteria Interventions Sakai Randomized controlled IHS criteria of migraine with or Zolmitriptan (zol) 1, 2. Triptan compared with placebo: Characteristics and outcomes Author Year Country Allowed other Method of Outcome Age Trial Name medications/ Assessment and Timing of Gender (Quality Score) interventions Assessment Ethnicity Other population characteristics Sakai Type(s) of rescue Primary efficacy endpoint: n=289 Without aura=64% 2002 medication approved 4- proportion of patients with avg age 38. Patients recorded 100% Japanese Vomiting=54% Fair quality migraine intensity on diary Photophobia=56% cards at 0. Severity: Moderate=73% Sheftell 2005 Recurrence of Primary efficacy endpoint Studies History of triptan use: USA headache were was time to onset of pain combined: N= Study 1: S50: 77% vs S100: allowed a second relief. Responses recorded 2696 79% vs placebo: 78% dose of study every 2 hours between Mean age: 40 Study 2: S50: 84% vs S100: medication, patients after dosing for 24 hour years 84% vs placebo: 84% with no relief after 2 periods. Patients rated Female: 85% hours weer allowed an pain relief and recurrence. White: 92% History of migraine without aura nonprohibited acute only: migraine medication Study 1: S50: 72% vs S100: 68% vs placebo: 71% Study 2: S50: 65% vs S100: 70% vs placebo: 67% *p<0. Triptan compared with placebo: Characteristics and outcomes Results Author Year Country Number screened/ Trial Name eligible/ Number withdrawn/ (Quality Score) enrolled lost to fu/analyzed Relief at various times Sakai nr/nr/289 58/289(20%) did not take medication; a further At.
Childhood outcomes philia and recurrent pregnancy loss: the LIVE-ENOX after prescription of antibiotics to pregnant women with study sildenafil 100mg without prescription. J Thromb Haemost 2005;3:227–9 spontaneous preterm labour: 7-year follow-up of the 72 purchase 75mg sildenafil with visa. Lancet 2008;372:1319–27 pregnancy in women with hereditary thrombophilia purchase sildenafil 50 mg without prescription. Prog- J Gynecol Obstet 2001;74:247–53 nosis for live birth in women with recurrent miscarriage: 73. Obstet Gynecol Aspirin plus heparin or aspirin alone in women with 2012;119:37–43 recurrent miscarriage. SPIN (Scottish of recurrent miscarriage for women with antiphospho- Pregnancy Intervention) study: a multicenter, rando- lipid antibody or lupus anticoagulant. Cochrane Database mized controlled trial of low-molecular-weight heparin Syst Rev 2012; in press and low-dose aspirin in women with recurrent mis- 61. 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Verkuyl INTRODUCTION The above does not mean that any contraceptive will do, as long as it is reliable: the client’s content- The challenge ment is an objective in itself. Her knowledge, the The human population was projected to hit 7 billion costs, the method selected, the service, her fears, by the second half of 2011. The newest estimates are her culture, her trust and the quality of counseling that we might stabilize at 9. Globally, 215 million women cannot get the • Pay attention to unwanted fertility but also to reproductive information and the contraceptives infertility that they want. If we solved this problem, according • Consider the possible need for contraception of to the World Health Organization (WHO), there nearly every patient aged >12 years that you see would be, over 5 years, 96 million fewer unintended • Discuss post-delivery contraception in the ante- pregnancies, 54 million fewer abortions, 110,000 natal period (for example in the ward while the fewer women dying in childbirth, 1. Being pregnant is more dangerous than using con- • Are out-of-office-hours services helpful? Therefore, the higher the typical failure 1,2 • Would exclusive FP services in a special clinic rate (Table 1) , the riskier a method is. From the deter some clients afraid to be identified by maternal mortality perspective, this failure rate is bystanders? Moreover, due to his production of green- house gases and consumption of non-renewable Some women have specific risk factors, such as resources, the typical Scandinavian has an ecologi- thrombophilia. While a pregnancy is still more cal footprint a hundred times larger than, for exam- dangerous for them than using combined hormonal ple, an Ethiopian. For example, many women do not return for IUDs after undergoing abortions although they said they would; or in a FP clinic if a woman is asked to come back later to have an IUD inserted [when the doctor is there or when she has (had) her period or when she has collected the (expensive? Or a postpartum sterilization is agreed on but there are too many emergencies or the delivery is on a Friday and she is asked to come back in 6 weeks, what percentage will not have the sterilization? Sterilization planned with a cesarean section but the doctor forgets, or the consent forms are lost; or pill prescribed but pharmacy in hospital closed or pill too expensive or out of stock; or clinic refers for hormonal EC: raped on Thursday, in police station Friday, seen in hospital Saturday after the pharmacy closed, no emergency stock available, told to come back Monday. FIRs, like typical use failure rates differ enormously per location. Adapted from: Trussel1 and Verkuyl2 contraception (LARC) or sterilization of either urine tests can’t exclude a pregnancy until 14 days partner is a better option. Eligibility for a method after ovulation and it may even take, with a normal (Boxes 1 and 2) becomes especially relevant if there pregnancy, another 4 days before a sensitive test is are options.
Toxicity proﬁles have been mild in the majority of early studies buy discount sildenafil 25mg line, without signiﬁcant myelosuppression over prolonged dosing cheap sildenafil 25mg mastercard. Due to these attractive attributes discount sildenafil 50 mg fast delivery, several agents targeting the BCR pathway are now entering early combination studies with traditional chemotherapeutics and/or other novel agents. It is clear that agents targeting the BCR pathway will signiﬁcantly affect the design of future therapeutic regimens for B-cell malignancies. Future research will focus on understanding potential mechanisms of resistance, identifying biomarkers of response, and deﬁning optimal combination regimens. The sequence of its IgH and IgL hypervariable B-cell non-Hodgkin lymphomas (NHLs) and leukemias comprise a regions (HVRs), which determine the speciﬁcity and afﬁnity of the complex group of malignancies with various clinical, histopatho- BCR to bind to antigenic determinants, is the unique molecular logic, and molecular features, as well as heterogeneous outcomes ﬁngerprint of each B cell and its clonal relatives. Patients who require treatment often receive from the BCR act through downstream signaling pathways to direct combination regimens with genotoxic agents and/or immunothera- the developmental stage, expansion, and survival of a normal B cell. Although initially effective in most cases, this approach is These pathways are also frequently used by B-cell malignancies to often complicated by signiﬁcant short- and long-term toxicities drive proliferation, growth, and survival and are the targets of including end-organ damage, myelosuppression, and secondary current BCR-related therapeutic approaches, rather than the BCR cancers. Relapse or transformation of indolent disease is not itself or its generation of signals. Salvage therapy is often associated with progressive resistance, and B-cell lymphoma/leukemia remains one of the “Active” BCR signaling, in which the BCR is activated by binding leading causes of cancer death in the United States. Therapies that target key cellular pathways/attributes speciﬁc for Because the cognate antigen for a particular BCR is usually not tumor cells are envisioned as a better way to treat cancer. In certain known, this binding is often experimentally modeled with an diseases, such as chronic myelogenous leukemia, targeted therapies antibody reagent derived from immunoglobulin generated in a have substantiated this vision. It has long been suspected that the nonhuman species and directed against constant regions of human B-cell receptor (BCR), the deﬁning attribute of normal and neoplas- IgH or IgL. BCR “cross-linking” with this reagent mimics the tic B cells, would be an effective target in BCR-expressing malignan- binding of polyvalent antigen and initiates a rapid cascade of cies. Recent years have seen a convergence of new preclinical evidence well-known proximal phosphorylation events, involving multiple that BCR signaling is critical to most B-cell malignancies, the kinases and adaptor molecules including Src family kinases (SFK, development of clinic-ready targeted agents inhibiting BCR-activated chieﬂy LYN), spleen tyrosine kinase (SYK), Bruton tyrosine kinase signaling pathways, and clinical trials demonstrating the striking (BTK), and PI3K. Active BCR signaling is therefore “druggable” effectiveness of these agents. Despite the success of BCR-targeting 1 by small-molecule inhibitors (SMIs) of several kinases, potentially therapy for B-cell malignancies, summarized in a recent review article, preventing the activation of one or more of the distal signaling questions remain about how best to translate BCR-targeting therapy to pathways that drive proliferation, growth, and survival: NF- B, the clinical setting. This review discusses brieﬂy the molecular biology NFAT, MAPK, and AKT/mTOR. Most evidence Molecular biology of BCR signaling in B-cell supporting this implication comes from chronic lymphocytic leuke- malignancies mia/small lymphocytic lymphoma (CLL/SLL), which can be di- A B cell is deﬁned and created by the productive rearrangement of vided into 2 types of cases. In unmutated (U) cases, the variable (V), immunoglobulin heavy (IgH) and light (IgL) chain genes, leading to diversity (D), and joining (J) segments of the IgH and IgL genes that Hematology 2013 553 have been selected by recombination to encode HVRs have ABC-DLBCL cell lines. Sequencing found that most of these lines, germline sequences. In mutated (M) cases, these segments have and 24% of primary ABC-DLBCL tumors, had mutations in the undergone somatic hypermutation, the normal process in germinal immunoreceptor tyrosine activation motif (ITAM) domains of centers by which the afﬁnity of BCR for its cognate antigen is CD79A and CD79B genes, which normally serve as substrates for increased. Both U and M cases display “stereotyped” nonrandom phosphorylation by SFK and activation of SYK via its tandem SH2 utilization of V, D, and J segments, and HVRs from some M cases domains. The molecular consequences of these ITAM mutations is have identical nucleotide sequences, both of which imply selection not entirely clear, although they appear to enhance BCR signaling for binding to a common self-antigen. Although the BCR of CLL by promoting surface BCR expression and reducing signal- cells has often been considered to resemble “natural” polyreactive terminating LYN kinase activity. Nonetheless, the frequency of antibodies characteristic of normal marginal zone B cells, speciﬁc these BCR-activating mutations in primary tumors is strong evi- antigens recognized by CLL/SLL cells have been identiﬁed, mostly dence for “chronic active” BCR signaling in ABC-DLBCL. Of of self-origin2,3 but also of fungal origin in some cases. After productive have nonstereotyped BCRs that bind to a common autoantigen in IgH rearrangement, early B-cell precursors in the BM express a the N-terminal region of vimentin. In the periphery, mature B cells continue to depend on tonic by the HVR: unusually frequent mutations in IgH scaffold regions BCR signaling, as shown by their disappearance upon conditional lead to abnormal sites of N-glycosylation in FL IgH chains,9 which 19 deletion of IgH or CD79A. In contrast, conditional deletion of may be bound by microenvironmental lectins and trigger BCR members of the CARD11/ BCL10/MALT1 complex, essential for signaling. Frequent (70%) mutations in TCF3 or its malignancies has additional implications. One is that self-reactivity negative regulator ID3 in BL cell lines and primary tumors were by B-cell malignancies implies a defect in tolerance mechanisms found to be associated with increased expression of IgH and IgL, that normally prevent development of self-reactive B cells. Al- and RNA interference studies showed dependence on CD79A and SYK but not CARD11. This was found to be the case for the activated B-cell (ABC) tions. In acute and chronic active BCR signaling, BTK is subtype of diffuse large B-cell lymphoma (DLBCL), originally phosphorylated by SYK and then phosphorylates phospholipase deﬁned by having a gene expression proﬁle with similarities to that C 2, leading to activation of protein kinase C beta and, in turn, of normal memory B cells activated by acute BCR cross-linking,14 CARD11. Ibrutinib (PCI-32765) is an orally available, selective and subsequently found to depend on NF- B activation by the kinase inhibitor that irreversibly binds to the Cys-481 residue of CARD11/ BCL10/MALT1 complex. Early preclinical studies demonstrated ibrutinib’s ability to found that the viability of most ABC-DLBCL cell lines was block BCR signaling in normal peripheral B cells and induce compromised by knock-down of several signaling proteins down- response in animals with lymphoma. No cumulative hematologic with 2 IgH and 2 IgL disulﬁde bond-linked chains to comprise the or nonhematologic toxicity was reported in patients with pro- BCR, were also found to be required for viability of BCR-dependent longed dosing. There was no signiﬁcant reduction in normal 554 American Society of Hematology Figure 1. Signaling through the B-cell receptor (BCR) leads to activation of multiple downstream kinases and is critical for cell survival. Agents are in early and late clinical development targeting key components of the cascade, including Bruton tyrosine kinase (BTK), PI3K, SYK, mammalian target of rapamycin (MTOR), and AKT appear promising with activity observed across B-cell malignancies. CK indicates cytokine; TLR, toll-like receptor; Ca, calcium; PIP3, phosphatidylinositol triphosphase; and PIP2, phosphatidylinositol biphosphate. B-cell or circulating immunoglobulin levels observed. A ﬂuores- ibrutinib with Waldenstrom macroglobulinemia attained a partial cent derivative of PCI-32765 was used to quantify BTK active response and phase 2 studies are now under way. Objective responses were reported in CC292 and ONO-WG-307 are 2 other BTK inhibitors in clinical multiple histologies, with signiﬁcant activity observed in the development. Preclinical models have demonstrated CC292’s abil- majority of patients with MCL and CLL; overall response rates 23 ity to form a highly selective covalent bond with the cysteine (ORR) were 78% and 69%, respectively. Preliminary results from an ongoing phase 1 study in relapsed hematologic malignancies suggest signiﬁcant activity in These preliminary ﬁndings prompted multiple phase 2 studies of CLL and some NHLs.
Atypical antipsychotic drugs and diabetes mellitus in a large outpatient population: a retrospective cohort study generic 100 mg sildenafil with mastercard. Frequency of new-onset diabetes mellitus and use of antipsychotic drugs among Central Texas veterans purchase sildenafil 25mg otc. Rate of new-onset diabetes among patients treated with atypical or conventional antipsychotic medications for schizophrenia 100 mg sildenafil overnight delivery. No significant difference in the risk of diabetes mellitus during treatment with typical versus atypical antipsychotics. Atypical antipsychotic drugs Page 198 of 230 Final Report Update 3 Drug Effectiveness Review Project 622. The incidence of diabetes in atypical antipsychotic users differs according to agent--results from a multisite epidemiologic study. Stress and the genesis of diabetes mellitus in schizophrenia. Mukherjee S, Decina P, Bocola V, Saraceni F, Scapicchio P. Jeste D, Lacro J, Bailey A, Rockwell E, Harris MJ, Caligiuri M. Lower incidence of tardive dyskinesia with risperidone compared with haloperidol in older patients. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Blind, controlled, long- term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol. A follow-up study of a population of schizophrenic patients treated with clozapine. Progress in Neuro Psychopharmacology & Biological Psychiatry. A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. Atypical antipsychotic drugs Page 199 of 230 Final Report Update 3 Drug Effectiveness Review Project Appendix A. Scales used to assess efficacy and adverse events The following narrative briefly describes each of the most commonly used assessment scales and summarizes methods of scoring and validation. The subsequent table lists abbreviations for all assessment scales noted in this review. The references cited here are listed at the end of this appendix. Population-Specific Scales Autism 1 The Aberrant Behavior Checklist (ABC), irritability subscale is rated by the parent or primary caretaker. The 15-item scale includes questions about aggression, self-injury, tantrums, agitation, and unstable mood on a scale of 0 to 45, with higher scores indicating greater severity. Each item is rated from 1 (not present) to 7 (extremely severe). Four factors have been derived from the items: Autism Factor (social withdrawal, rhythmic motions/stereotype, abnormal object relations, unspontaneous relation to examiner, underproductive speech), Anger/Uncooperativeness Factor (angry affect, labile affect, negative and uncooperative), Hyperactivity Factor (fidgetiness, hyperactivity, hypoactivity), and Speech Deviance Factor (speech deviance, low voice). Bipolar I Disorder The Young Mania Rating Scale (YMRS) is an 11-item, clinician-administered interview scale designed to quantify the severity of mania. Clinicians select from 5 grades of severity specific to each item when making YMRS ratings. Clinical trials of individuals with Bipolar I Disorder generally required scores equal to or greater than 20 for enrollment and specified scores equal to or below 12 as representing symptomatic remission. One validity study reported high correlations between the YMRS and the Petterson Scale (r=0. Dementia 4 The BEHAVE-AD assesses 25 behaviors in the following 7 areas: paranoid and delusional ideation, hallucinations, activity disturbances, aggressiveness, diurnal rhythm disturbances, affective disturbance, and anxieties and phobia. Caregivers rate the presence and severity of each item over the preceding 2 weeks on a 4-point scale (0=not present; 1=present; 2=present, generally with an emotional component; 3=present, generally with an emotional and physical component). The frequency and severity of each behavior is determined by a series of questions posed to the caregiver. Severity is graded 1, 2, or 3 (mild, moderate, or severe) and frequency is rated on a scale of 1 through 4 (1=occasionally, less than once per week; 4=very frequently, once or more per day or continuously). The maximum score for each domain is 12 Atypical antipsychotic drugs Page 200 of 230 Final Report Update 3 Drug Effectiveness Review Project (frequency multiplied by severity). The total score is the sum of the individual domain scores, for a maximum possible score of 144. Some trials in patients with dementia used the NPI-Nursing Home Version (NPI-NH), which has been validated for use in nursing homes. Caregivers administer the scale after receiving training. The frequency of each behavior is scored with reference to the previous 2 weeks on a 7-point scale (1=never, 2=less than one time per week, 3=one to 2 times per week, 4=several times per week, 5=once or twice per day, 6=several times per day, 7=several times per hour). Disruptive Behavior Disorders 7 The Nisonger Child Behavior Rating Form was developed for children with developmental disabilities. The Parent version has two positive/social subscales (Compliant/Calm and Adaptive/Social) comprising 10 items. It has 66 Problem Behavior items that score onto 6 subscales: Conduct Problem, Insecure/Anxious, Hyperactive, Self-Injury/Stereotypic, Self- Isolated/Ritualistic, and Overly Sensitive. It is scored from 1 (no aggression reported) to 5 (intolerable behavior). Schizophrenia The Positive and Negative Syndrome Scale (PANSS) is a 30-item instrument designed to assess schizophrenia symptoms. Each item is rated using a 7-point severity scale (1=absent, 2=minimal, 3=mild, 4=moderate, 5=moderate-severe, 6=severe, 7=extreme). The PANSS is administered by qualified clinicians using combinations of unstructured, semistructured, and structured interview strategies. The PANSS is composed of three subscales, a 7-item Positive Scale, a 7-item Negative Scale and a 16-item General Psychopathology Scale. The PANSS also provides a method of assessing relationships of positive and negative syndromes to one another and to general psychopathology. High correlations between the PANSS Positive Syndrome Scale and the Scale for the Assessment of Positive Symptoms (SAPS) (r=0. Atypical antipsychotic drugs Page 201 of 230 Final Report Update 3 Drug Effectiveness Review Project Scales for General Use Extrapyramidal Side Effect Scales 10 The Barnes Akathisia Scale (BAS) is a tool used for diagnosis of drug-induced akathisia.