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Some day we will have powerful targeted therapies for autoimmune diseases. Remission will be induced efficiently. Side effects will be mere ripples. Unfortunately, that day is not imminent. Current therapies are powerful but with ...
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Some day we will have powerful targeted therapies for autoimmune diseases. Remission will be induced efficiently. Side effects will be mere ripples. Unfortunately, that day is not imminent. Current therapies are powerful but with unintended targets and side effects that can be equivalent to a sea change. For SLE, the current competition to select the 'gold standard' immunosuppressant has come down to two regimens: intravenous cyclophosphamide (IVCY, standard NIH protocol or its variations) versus oral mycophenolate (MMF). Until recently, IVCY reigned as the gold standard, a title it achieved through a curious journey that did not involve rigorous head-to-head competition. Oral cyclophosphamide (POCY) has not been invited to the current competition to select the gold standard immunosuppressant despite the substantial evidence that POCY can perform at least as well as IVCY or mycophenolate, and compared to IVCY, is far less expensive, easier for the patient, and maybe more effective in African-Americans. Here, we state the case for POCY as therapy for severe autoimmune diseases. We suggest that if POCY is allowed to compete, it will not disappoint.
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Although, most patients respond initially to therapy for nephrotic syndrome, about 70% of patients have a relapse. Currently, there is no consensus about the most appropriate second-line agent in children who continue to suffer a ...
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Although, most patients respond initially to therapy for nephrotic syndrome, about 70% of patients have a relapse. Currently, there is no consensus about the most appropriate second-line agent in children who continue to suffer a relapse. This network meta-analysis was designed to compare the efficacy and safety of the commonly used immunosuppressive agents in second-line therapeutic agents (ie, cyclophosphamide, cyclosporine, tacrolimus and mycophenolate mofetil) for refractory childhood nephrotic syndrome. MEDLINE, Cochrane, EMBASE and Google Scholar databases were searched until October 17, 2015 using the following search terms: cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil and childhood nephrotic syndrome. Randomized controlled trials, prospective 2-arm studies and cohort studies were included. 7 studies with 391 patients were included. Bayesian network meta-analysis found that treatment with mycophenolate mofetil had the greatest odds of relapse compared with tacrolimus (pooled OR=49.72, 95% credibility interval (CrI) 1.65 to 2483.32), cyclophosphamide (pooled OR=72.05, 95% CrI 1.44 to 13633.33) and cyclosporine (pooled OR=11.42, 95% CrI 1.03 to 131.60). Rank probability analysis found cyclophosphamide was the best treatment with the lowest relapse rate as compared with other treatments (rank probability=0.58), and tacrolimus was ranked as the second best (rank probability=0.38). Our findings support the use of cyclophosphamide and tacrolimus in treating children with relapsing nephrotic syndrome.
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Nevertheless, I think I have a very rudimentary understanding of the basic theory of the physiologic mechanisms invoked by the VAC. Here goes. Subatmospheric pressure is communicated via open-cell polyurethane foam sponges cut to ...
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Nevertheless, I think I have a very rudimentary understanding of the basic theory of the physiologic mechanisms invoked by the VAC. Here goes. Subatmospheric pressure is communicated via open-cell polyurethane foam sponges cut to fit the given wound contour. Tissue blood supply essential for transport of oxygen and removal of evil metabolites is indirectly enhanced by the removal of excess interstitial fluid with a resulting diminution of tissue turgor.1 Local edema is thereby controlled, excess fluid drainage evacuated, development of healthy granulation tissues promoted, and wound bacterial counts decreased.1 Since typically, VAC dressings are changed only every other day, this reduction in the frequency of dressing changes reduces but does not eliminate all pain suffered by the patient. The nursing burden is also lessened so that extra time hopefiilly will be spent on other patient issues. A related indirect benefit is that the deleterious risk of wound dessication or other untoward sequela if dressing changes are postponed or even sometimes omitted by a busy nursing staff can be minimized. Some even proselytize a paradigm shift in that the VAC allows a revision downward of the "reconstructive ladder," so that perhaps the free flap can even become passe.2 And all of this will be accomplished less expensively with shorter hospital stays.
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Background: Cyclophosphamide has transformed the outcome of ANCA-associated vasculitis, but it is highly toxic. Recent studies have suggested that pulsed intravenous cyclophosphamide (pCyc) is an effective alternative with less co...
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Background: Cyclophosphamide has transformed the outcome of ANCA-associated vasculitis, but it is highly toxic. Recent studies have suggested that pulsed intravenous cyclophosphamide (pCyc) is an effective alternative with less complications, but may lead to an increased rate of relapse. However, these studies used relatively short courses of treatment with cyclophosphamide. In this study we used a prolonged course of low-dose intravenous cyclophosphamide for 18-24 months for ANCA-associated vasculitis, evaluated the effectiveness of pCyc and analysed the outcome of a prolonged treatment on the rate of relapse. Methods: A retrospective analysis of all the patients treated with pCyc from 1995 to 2002 was performed. Results: Thirty-seven patients were followed for an average of 38 months. Thirty-four of 37 patients (91.9%) achieved complete remission at 3 months. Eight (21%) episodes of relapse occurred in 7 patients. The cyclophosphamide was well tolerated with a low rate of infections (18.9%) and 1 death (2.7%) due to sepsis whilst on cyclophosphamide. Conclusion: In this study, pCyc was effective in achieving rapid remission and had a low complication rate. If prolonged, this treatment may reduce the rate of relapse.
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Severe hemorrhagic cystitis associated with oral cyclophosphamide (CYP) therapy has rarely been reported in the past 20 years, probably because this condition has largely disappeared because of the use of shorter courses of CYP, e...
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Severe hemorrhagic cystitis associated with oral cyclophosphamide (CYP) therapy has rarely been reported in the past 20 years, probably because this condition has largely disappeared because of the use of shorter courses of CYP, either oral or IV. Herein, we describe a patient who received 309 g of oral CYP over a 4-year period to treat Wegener’s granulomatosis (WG) that initially involved brain, lung, and kidney. She came under our care for the first time when she presented with a one-day history of oliguria and passing blood clots. Severe hemorrhagic cystitis was present. It eventually required cystectomy. Despite her massive CYP exposure her kidney biopsy showed acute crescentic glomerulonephritis. She survived her acute illness only to die 2 months later of acute leukemia. This patient is a reminder that severe hemorrhagic cystitis from oral CYP still exists, and that WG can be resistant to even toxic doses of oral CYP. Alternative therapies are discussed.
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Purpose Genetic variation in the activation of the prodrug cyclophosphamide (CP) by cytochrome P450 (CYP) enzymes has been shown to influence outcomes. However, CYP are also subject to phenoconversion due to either the effects of ...
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Purpose Genetic variation in the activation of the prodrug cyclophosphamide (CP) by cytochrome P450 (CYP) enzymes has been shown to influence outcomes. However, CYP are also subject to phenoconversion due to either the effects of comedications or cancer associated down-regulation of expression. The aim of this study was to assess the relationship between CP bioactivation with CYP2B6 and CYP2C19 genotype, as well as CYP2C19 phenotype, in breast cancer patients. Methods CP and the active metabolite levels were assessed in breast cancer patients (n = 34) at cycle 1 and cycle 3 of treatment. Patients were genotyped for a series of SNP known to affect CYP2B6 and CYP2C19 function. The activity of CYP2C19 was also assessed using a probe drug. Results We found a significant linear gene-dose relationship with CYP2B6 coding SNP and formation of 4-hydroxycyclophosphamide. A possible association with CYP2C19 null genotype at cycle 1 was obscured at cycle 3 due to the substantial intra-individual change in CP bioactivation on subsequent dosing. Conclusion Comedications may be the cause for this inter-occasion variation in bioactivation of cyclophosphamide and the ensuing phenoconversion may account for the conflicting reports in the literature about the relationship between CYP2C19 genotype and CP bioactivation pharmacokinetics. Trial registration ANZCTR363222 (6/11/2012, retrospectively registered).
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Allogeneic hematopoietic cell transplant (Allo-HCT) is a potentially curative therapy for many malignant and nonmalignant hematological diseases. However, a suitable human leukocyte antigens (HLAs)-matched donor may not be availab...
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Allogeneic hematopoietic cell transplant (Allo-HCT) is a potentially curative therapy for many malignant and nonmalignant hematological diseases. However, a suitable human leukocyte antigens (HLAs)-matched donor may not be available when the patient is in urgent need of a stem cell transplant. This challenge has been ameliorated to a large extent by the introduction of haploidentical donors. This type of donor shares one HLA haplotype with the recipient. Therefore, a patient's full sibling has a 50% chance of being haploidentical and a patient's biologic parents and children will all be haploidentical, thus providing an immediately accessible, motivated donor for almost every recipient. Haploidentical transplants previously incurred prohibitively poor outcomes, preventing their widespread use. However, several recent advances have dramatically improved the results, making them a more viable donor source. In this review, we discuss different types of donors used for Allo-HCT with a particular focus on the use of haploidentical donors and their future potential.
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A series of thymidine and tetrahydrofurfuryl phosphoramidates bearing haloethyl or piperidyl sulostituents was synthesized and used to investigate the activation mechanisms of nucleoside phosphoramidate prodrugs. Structure assignm...
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A series of thymidine and tetrahydrofurfuryl phosphoramidates bearing haloethyl or piperidyl sulostituents was synthesized and used to investigate the activation mechanisms of nucleoside phosphoramidate prodrugs. Structure assignments for the tetrahydrofurfuryl reaction products were confirmed by comparison to authentic samples. Structural assignments for thymidine phosphoramidate reaction products were made by analogy to the tetrahydrofurfuryl products. Generation of the phosphoramidate anion leads to cyclization and subsequent nucleophilic attack at carbon and phosphorus of the resulting aziridinium ion intermediate to give the observed products. Nucleophilic attack by water at carbon and phosphorus occurs without selectivity, supporting a mechanism of action of haloethylamine nucleoside prodrugs involving intracellular release of the nucleotide. Activation of the benzotriazolyl piperidyl phosphoramidates is followed by P-N bond hydrolysis; this reaction is subject to specific acid catalysis and to nucleophilic catalysis by 1-hydroxybenzotriazole. These results suggest that the mechanism of action of the piperidyl nucleoside phosphoramidates involves the intracellular release of the active nucleotide following P-N bond cleavage, presumably by the action of an endogenous phosphoramidase. [References: 15]
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