By K. Urkrass. Roanoke College.
As we progress in understanding the basis for quantita- ance induction similar to that seen with inhibitors to FVIII has been tive deﬁciencies in type 1 disease purchase 400mg hoodia visa, we may be able to increase reported buy cheap hoodia 400 mg on-line. Newer treatment strategies may focus on enhancing endogenous produc- Future therapies tion and release or prolonging the half-life of VWF infusions for Recombinant VWF prolonged efﬁcacy and convenience of patients buy hoodia 400mg online. Recombinant FVIII and factor IX have been available for many years cheap hoodia 400 mg without a prescription, but only recently has rVWF been studied in clinical trials. In a Acknowledgments pharmacokinetic and safety study, rVWF-rFVIII compared favor- The authors thank our hemostasis staff for their tireless efforts in ably to plasma-derived VWF-FVIII. Recovery, as measured by caring for bleeding disorder patients: Julie Thomas, Kelly Dawson, VWF:RCo activity assay, was quite similar, but rVWF-rFVIII Shelley Ploch, Johnna Oleis, Lyndsey Rollins, Pamela Krueger, and infusions produced a slightly lower VWF:Ag level, demonstrating a Kim Blittle. This higher ratio of activity is due to the increased Disclosures relative amount of ultra-large-molecular weight multimers in the Conﬂict-of-interest disclosures: A. In theory, this could lead ticals, and the American Board of Internal Medicine and has to thrombotic complications, but studies of the patient plasma received research funding from NovoNordisk. Off-label drug stabilization of endogenous FVIII by the rVWF that produced a use: Oral contraceptives for VWD. This may allow the infusion of only rVWF if there is no immediate need for FVIII:C to avoid the Correspondence excessive rise in FVIII:C when plasma-derived concentrates are Anne T. Neff, MD, Vanderbilt University; Phone: (615)936-0381; infused for several doses. Acute bleeding situations in type 3 Fax: (615)343-3694; email: anne. Therapeutic trials with rVWF References are ongoing. Thrombocytopenia is a signiﬁcant problem in patients with VWD 2. A new pharmacolog- VWF A1 domain and the platelet GPIb receptor. Desmopressin is ical approach to the management of hemophilia and von Willebrand known to produce a drop in platelet counts if given to patients with disease. Kaufmann JE, Oksche A, Wollheim CB, Gunther G, Rosenthal W, blocked this fall in platelet count37 and, in a different trial, led to a Vischer UM. Vasopressin-induced von Willebrand factor secretion rise in baseline platelet count and VWF:RCo and FVIII:C levels, from endothelial cells involves V2 receptors and cAMP. Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease:results of a multicenter European study. Recombinant human IL-11 (rhIL-11) or oprelvekin (Neumega) is a 6. Haberichter SL, Balistreri M, Christopherson P, et al. Assay of the von US Food and Drug Administration (FDA)–approved drug indicated Willebrand factor (VWF) propeptide to identify patients with type 1 von for the prevention of severe thrombocytopenia after myelosuppres- Willebrand disease with decreased VWF survival. Revel-Vilk S, Schmugge M, Carcao MD, Blanchette P, Rand ML, 540 American Society of Hematology Blanchette VS. Desmopressin (DDAVP) responsiveness in children with 26. Ranger A, Manning RA, Lyall H, Laffan MA, Millar CM. Effects of oral contraceptives on blood coagulation: a 27. Willebrand disease type 3 during pregnancy - 2 cases reports. Women and von Willebrand disease: controversies in Med Pharmacol Sci. Federici AB, Sacco R, Stabile F, Carpenedo M, Zingaro E, Mannucci forms of von Willebrand’s disease:results from the von Willebrand PM. Optimising local therapy during oral surgery in patients with von Disease Prophylaxis Network (VWD PN).
In the small dual therapy trial cheap hoodia 400mg, patients receiving the 2 drugs reported a total of 59 episodes of hypoglycemia; rosiglitazone monotherapy-treated patients reported only 4 episodes in total purchase 400mg hoodia overnight delivery. Cardiovascular events Two patients in the Avandaryl trial reported congestive heart failure: 1 in the glimepiride group and 1 in the higher-dose Avandaryl hoodia 400 mg mastercard. No cardiovascular events were reported in the dual therapy study buy cheap hoodia 400 mg line. Gastrointestinal events None were reported in either trial. Edema Edema reports were fairly consistent across arms of the Avandaryl trial and ranged from 2. No episodes of edema were reported in the dual therapy study. Weight change Patients in all arms of the Avandaryl trial gained weight. There appeared to be a dose-repose association between the 2 Avandaryl arms: patients on lower-dose Avandaryl gained 2. In the dual therapy v rosiglitazone trial, all patients gained weight: 5. Total cholesterol In the Avandaryl trial, mean total cholesterol increase was significant in the rosiglitazone and Avandaryl arms. The largest increase was in the rosiglitazone arm (21. There was no significant difference in cholesterol levels between dual therapy and rosiglitazone. Other adverse events Headache and nasopharyngitis were reported in roughly 4% of patients in each arm of the Avandaryl trial. Adverse effects of Avandaryl (rosiglitazone + glimepiride) and rosiglitazone/glimepiride dual therapy in adults with type 2 diabetes 186 187 Chou 2008 McCluskey 2004 Avandaryl Avandaryl Dual 4 mg/4 mg 8 mg/4 mg Glimepiride Rosiglitazone therapy Rosiglitazone Withdrawals due to adverse 3. This 24-week RCT (N=600) compared Actoplus Met (30 mg/1,700 mg daily) with pioglitazone alone (30 mg daily) and metformin alone (1,700 mg 139 daily). Overall incidences of adverse events were similar across treatment arms: 50. Reports of severe adverse events were also similarly distributed among the arms: 1. A 15 month trial (N=271) compared dual therapy with pioglitazone and metformin to monotherapy with each component (3 month run-in/titration phase, 12 month full-dose treatment 188 and follow-up phase). Very little harms information was reported in this trial. Table 68 summarizes adverse effects of Avandaryl (rosiglitazone + glimepiride) and rosiglitazone/glimepiride dual therapy in adults with type 2 diabetes. Mortality and withdrawals Fewer withdrawals from the FDCP study due to adverse events occurred in the Actoplus Met and pioglitazone alone arms compared with the metformin alone arm (3. Hypoglycemia In the FDCP trial, rates of hypoglycemia (defined as fasting plasma glucose <60 mg/dL) were low in all treatment arms: 1. In the dual therapy study, 3 patients in the dual therapy arm withdrew due to hypoglycemia (defined as above). Cardiovascular events There were no episodes of congestive heart failure during the FDCP trial. Three patients in the monotherapy arms (2 on pioglitazone and 1 on metformin) showed clinically significant worsening ECG results from baseline to end of follow-up. One pioglitazone patient was found to have coronary artery disease and myocardial infarction; the other was diagnosed with arterial branch block. The metformin patient was determined to have myocardial ischemia.
Venlafaxine compared with sertraline One study determined efficacy and safety of venlafaxine (25-100 mg/d) compared to sertraline 293 (18 generic hoodia 400 mg overnight delivery. We graded the quality of this study as poor for efficacy because of high loss to follow-up (44 discount hoodia 400mg line. The investigators reported a significantly higher rate of withdrawal among venlafaxine- than sertraline-treated patients (63% compared with 24%) order hoodia 400mg with mastercard. In addition order 400mg hoodia with mastercard, venlafaxine-treated patients had a significantly higher rate of severe adverse events (P=0. Venlafaxine compared with SSRIs A pooled data analysis combined original data from eight comparable, double-blind, active- 294, 295 controlled, randomized trials. A primary objective of this analysis was to determine differences in response and remission based on sex and age. This study was not based on a systematic literature search, so results must be viewed cautiously. For venlafaxine-treated 295 patients, neither age (< 50 or > 50 years of age) nor sex affected remission rates. Among patients treated with SSRIs, however, a significant interaction was observed between treatment and sex (P=0. Remission rates for older women treated with venlafaxine (48%) were higher than remission rates for older women treated with SSRIs (28%, P=0. Hormone replacement therapy appeared to eliminate these differences. Additional analyses of age subgroups (< 40, 41- 54, 55-64, and > 65 years of age) and sex subgroups revealed that no significant age-by- treatment, sex-by-treatment, or age-by-sex-by-treatment interactions occurred. Men and women of different ages within each treatment group had similar rates of remission, response, and 294 absence of depressed mood. Among patients over 40 years of age, the rates of adverse events were similar between the treatment groups, although venlafaxine-treated patients aged 55 to 64 years reported significantly more nausea than placebo (P<0. Bupropion compared with paroxetine One fair RCT examined the efficacy of bupropion SR (100-300 mg/d) and paroxetine (10-40 111, 112 mg/d) in 100 outpatients ages 60 years or older (range 60-88 years) over 6 weeks. The majority of patients were white (bupropion SR, 98%; paroxetine, 90%), female (bupropion SR, Second-generation antidepressants 92 of 190 Final Update 5 Report Drug Effectiveness Review Project 54%; paroxetine, 60%), and did not use antidepressants for the current episode before enrollment (bupropion SR, 83%; paroxetine, 88%). The overall loss to follow-up was 16 percent with no significant difference between treatment groups. Efficacy according to any outcome measure did not differ significantly between treatment groups. Response rates (≥ 50% reduction in HAM-D scores) were similar in both groups (bupropion SR, 71%; paroxetine, 77%). Quality-of-life scales (QLDS, SF-36) showed statistically significant improvements in both treatment groups from baseline to endpoint (P<0. Ethnicity No studies directly compared the efficacy, effectiveness and harms of second-generation antidepressants among different races or ethnicities. Therefore, we summarize results of studies that compared second-generation antidepressants with placebo. Duloxetine compared with placebo Two pooled analyses of seven placebo-controlled duloxetine trials assessed the efficacy and 296 297 tolerability of duloxetine in Hispanic and African American patients compared to Caucasian patients. The first analysis included 1,342 Caucasians and 120 Hispanics and found no difference 296 in efficacy outcomes for Hispanics and Caucasians. There were no significant differences between groups in discontinuation rates due to adverse events ir in the types or occurrence of specific adverse events. The second analysis of 1,300 Caucasians and 123 African Americans also found no evidence for a differential effect of duloxetine in African-American and Caucasian 297 patients in efficacy or safety outcomes. Fluoxetine compared with placebo An RCT examined ethnic differences in response to antidepressant treatment among depressed 298 HIV-positive patients.
In the DUET studies cheap 400mg hoodia visa, 17 RAMs for etravirine were identified: V90I order hoodia 400 mg overnight delivery, A98G purchase 400 mg hoodia mastercard, L100I purchase 400 mg hoodia amex, K101E/H/P, V106I, E138A, V179D/F/T, Y181C/I/V, G190A/S and M230L. Based on these, an etravirine resistance score was developed. A weighting factor of 3 was attrib- uted to Y181I/V, followed by a weighting factor of 2. The mutations E138A, V106I, G190S, and V179F received a weighting factor of 1. In a panel of 4,248 NNRTI-resistant clinical HIV-1 isolates, the mutations with the highest weight, Y181I and Y181V, had a low prevalence of 1. The mutation Y181C, which is selected more frequently in patients taking nevirapine than efavirenz, had a prevalence of 32% (Vingerhoets 2008). E138A/G, V179E, G190Q, M230L and K238N received 3 points; 101E, V106A / I, E138K, V179L, Y188L and G190S received 2 points. V90I, A98G, K101H, K103R, V106M, E138Q, V179D/F/I/M/T, Y181F, V189I, G190A/E/T, H221Y, P225H, and K238T contributed with 1 point. A loss of efficacy is likely with a total score of 4 or higher (Haddad 2010). Rilpivirine is also effective against single NNRTI RAMs such as K103N, V106A, G190S/A; in vitro the following mutations were selected: V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C and M230I/L (Azijn 2009). In a clinical study involving treatment-naïve patients without any (known) NNRTI mutations most of the in vitro mutations were confirmed (K101E, K103N, E108I, E138K/R, Y181C und M230L) (Molina 2008). The cross-resistance between rilpivirine and etravirine is greater than 90% (Porter 2013). Six key muta- tions at 5 positions could be identified for rilpivirine using a data set of 187 geno-/ phenotype pairs: L100I, K101P, Y181I/V, G190E and F227C. Similar to etravirine, K101H, E138G, V179F and M230L were further relevant mutations (Melikian 2014). In the Phase III studies ECHO und THRIVE, virological failure was more frequent on rilpivirine than on efavirenz (10. RAMs were more common in patients failing on rilpivirine than on efavirenz (63% versus 54%). The most common mutations were E138K (45%), K101E (13%), H221Y (10%), V189I (8%), Y181C (8%) and V90I (8%). In 46%, 31% and 23% of resistant isolates respectively, 1, 2 or 3 NNRTI mutations were detected. Overall, 15 RAMs were identified as being associated with a decreased susceptibility to rilpivirine: K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C, M230I/L. These RAMs were identified either (a) in vitro as HIV-1 SDMs conferring phenotypic resistance to rilpivirine (K101P, Y181I, and Y181V with fold-changes in IC50 of 51. Cross-resistance to etravirine was commonly observed among patients failing rilpivirine (>90%) (Rimsky 2012). Besides NNRTI mutations, NRTI mutations were also more frequent among treatment failures on rilpivirine (68% versus 32%) – with primarily M184I on rilpivirine and M184V on efavirenz. Protease Inhibitors (PIs) Boosted PIs are a drug class with a high genetic barrier. Generally, several RAMs are required for complete loss in efficacy. As seen with numerous other antiviral agents, continuation of a failing PI regimen leads to the development of further mutations, which ultimately results in moderate to high cross-resistance between PIs. If treatment is changed early on to another PI combi- nation, i. In first-line therapy with ritonavir-boosted PIs the emergence of major PI mutations is rare and has been observed infrequently (Conradie 2004, Friend 2004, Coakley 2005b, Lataillade 2008).