ASHAP: a regimen for cytoreduction of refractory or recurrent Hodgkin's disease.
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Patients with Hodgkin's disease, which is either refractory or recurs after frontline chemotherapy with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), or both regimens, generally have a poor prognosis. High-dose chemotherapy with autologous marrow or stem cell rescue (ABMT) is now a widely used salvage strategy in these patients. In this study, our objective was to determine the response rate to ASHAP (Adriamycin = doxorubicin, Solumedrol = methylprednisolone, High-dose Ara-C = cytosine arabinoside, and Platinum = cisplatinum), in a group of patients with Hodgkin's disease with such poor risk characteristics. The treatment was intended as a brief tumor reducing program before ABMT. Fifty-six patients with diagnosed relapsed or primary refractory Hodgkin's disease underwent this treatment. The program consisted of the administration of two cycles of ASHAP chemotherapy (doxorubicin 10 mg/m2/d intravenous (IV) continuous infusion (CI) over 24 hours, days 1 to 4; methylprednisolone 500 mg/d IV over 15 minutes daily for 5 days; cisplatinum 25 mg/m2/d IV CI over 24 hours, days 1 to 4; cytosine arabinoside 1.5 g/m2/d IV over 2 hours on day 5). After two courses of ASHAP the patients were evaluated for response, including a gallium scan test. Patients with progressive disease were taken off the study. Those with responding or stable disease received a third course of ASHAP, followed by consolidative treatment with ABMT. There were 19 complete responses (34% CR), 20 partial responses (36% PR), and 17 treatment failures, including 8 with minor responses and 9 with disease progression. Thus, in total there were 39 responses out of 56 patients (CR + PR = 70%). Myelosuppression was the main toxicity. There were no deaths due to toxicity. At this time, 23 patients are alive. There were 31 deaths due to disease progression and 2 due to other causes. The initial response to ASHAP before subsequent ABMT consolidation treatment correlated with survival. All 17 patients in whom ASHAP failed to achieve a response have died. The presence of B symptoms at relapse, and a duration of response to the last regimen of +info)
Therapeutic time window for methylprednisolone in spinal cord injured rat.
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Recent clinical trials have reported that methylprednisolone sodium succinate administered within 8 hours improves neurological recovery in human spinal cord injury (SCI). Methylprednisolone, however, was ineffective and possibly even deleterious when given more than 8 hours after injury. This finding suggests that a therapeutic time window exists in spinal cord injury. In order to determine the doses, durations and timing of methylprednisolone treatment for optimal neuroprotection, a single or two bolus dose of methylprednisolone (30 mg/kg) was administered at 10, 30, 120, 150 and 240 min. after three graded spinal cord injury. The primary outcome measure was 24-hour spinal cord lesion volumes estimated from spinal cord Na+ and K+ shifts. A single 30 mg/kg dose of methylprednisolone at 10 min. after injury significantly reduced 24-hour lesion volumes in injured rat spinal cords. However, any other methylprednisolone treatment starting 30 min. or more after injury had no effect on 24-hour lesion volumes compared to the vehicle control group. Moreover, delayed treatment increased lesion volumes in some cases. These results suggest that the NYU SCI model has a very short therapeutic window. (+info)
The effects of pulse methylprednisolone on matrix metalloproteinase and tissue inhibitor of metalloproteinase-1 expression in rheumatoid arthritis.
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OBJECTIVE: To investigate the effects of a 1000 mg i.v. pulse of methylprednisolone succinate (pulse therapy) on the expression of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in the synovial membrane of the knee in patients with rheumatoid arthritis (RA). METHODS: Sequential arthroscopic biopsies of the knee were taken before and 24 h after pulse therapy (11 patients), at disease relapse (three patients) and after retreatment with pulse therapy (one patient). Immunoperoxidase staining for MMP-1 (interstitial collagenase), MMP-3 (stromelysin-1) and TIMP-1 was performed and the immunoreactive staining quantified by colour video image analysis. RESULTS: In the synovial lining layer, MMP-1 and TIMP-1 immunostaining was reduced by a mean of 47% (P = 0.02) and 72% (P = 0.05), respectively, 24 h after pulse methylprednisolone therapy. In the synovial sublining layer, MMP-1 was reduced by a mean of 51% (P = 0.08) and TIMP-1 by a mean of 73% (P = 0.02) 24 h after pulse methylprednisolone therapy. There was no change in MMP-3 staining in the synovial lining or sublining layer. CONCLUSIONS: High-dose pulse methylprednisolone therapy is associated with a rapid (within 24 h) and substantial decrease in the expression of MMP-1 and TIMP-1 but not MMP-3 in the synovial membrane in RA. (+info)
Ensheathing cells and methylprednisolone promote axonal regeneration and functional recovery in the lesioned adult rat spinal cord.
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Axons fail to regenerate after spinal cord injury (SCI) in adult mammals, leading to permanent loss of function. After SCI, ensheathing cells (ECs) promote recovery in animal models, whereas methylprednisolone (MP) promotes neurological recovery in humans. In this study, the effectiveness of combining ECs and MP after SCI was investigated for the first time. After lesioning the corticospinal tract in adult rats, ECs were transplanted into the lesion, and MP was administered for 24 hr. At 6 weeks after injury, functional recovery was assessed by measuring successful performance of directed forepaw reaching (DFR), expressed as percentages. Axonal regeneration was analyzed by counting the number of corticospinal axons, anterogradely labeled with biotin dextran tetramethylrhodamine, caudal to the lesion. Lesioned control rats, receiving either no treatment or vehicle, had abortive axonal regrowth (1 mm) and poor DFR success (38 and 42%, respectively). Compared with controls, MP-treated rats had significantly more axons 7 mm caudal to the lesion, and DFR performance was significantly improved (57%). Rats that received ECs in combination with MP had significantly more axons than all other lesioned rats up to 13 mm. Successful DFR performance was significantly higher in rats with EC transplants, both without (72%) and with (78%) MP, compared with other lesioned rats. These data confirm previous reports that ECs promote axonal regeneration and functional recovery after spinal cord lesions. In addition, this research provides evidence that, when used in combination, MP and ECs improve axonal regrowth up to 13 mm caudal to the lesion at 6 weeks after injury. (+info)
Heart xenograft survival with chimeric pig donors and modest immune suppression.
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OBJECTIVE: To assess the use of donor pigs with cellular chimerism for prevention of acute rejection with modest immune suppression. The clinical use of pig organ xenografts is currently precluded by severe acute rejection, which resists standard immune suppression. SUMMARY BACKGROUND DATA: For long-term survival of pig organ xenografts, immune suppression significantly greater than used with allografts would currently be necessary, leaving the recipient immune deficient and at increased risk for infections. Induction of immune tolerance and tissue accommodation could enhance xenograft survival but would lead to complications and frequent graft failure. Induction of cellular chimerism within the donor pigs, however, could accomplish these goals before transplantation, significantly reducing the risk. METHODS: Marrow cells from sheep were infused into fetal pigs. Heart xenografts from chimeric or nonchimeric pigs were transplanted heterotopically into recipient sheep, simultaneous with infusion of splenocytes. Posttransplant suppression consisted of cyclosporine and tapered corticosteroids, comparable with allotransplants. RESULTS: All of the control grafts (n = 12) were rejected by acute vascular rejection in 4 to 8 days. In contrast, only one episode of vascular rejection was observed in the experimental group (n = 13). Four experimental recipients had an episode of moderate diffuse cellular rejection (grade 3) and one had moderate focal cellular rejection (grade 2). Each episode responded to pulse steroids. Seven grafts showed no significant rejection. There was little evidence of immune deficiency, infection, or toxicity. CONCLUSIONS: Acute vascular rejection was prevented in a large animal model without the need for severe immune suppression. (+info)
The 'crashing asthmatic.'.
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Asthma is a common chronic disorder, with a prevalence of 8 to 10 percent in the U.S. population. From 5 to 10 percent of patients have severe disease that does not respond to typical therapeutic interventions. To prevent life-threatening sequelae, it is important to identify patients with severe asthma who will require aggressive management of exacerbations. Objective monitoring of pulmonary status using a peak flow meter is essential in patients with persistent asthma. Patients who have a history of fragmented health care, intubation, or hospitalization for asthma and those with mental illness or psychosocial stressors are at increased risk for severe asthma. Oxygen, beta2 agonists, and systemic corticosteroids are the mainstays of acute asthma therapy. Inhaled anticholinergic medications provide additional bronchodilation. In patients who deteriorate despite usual therapeutic efforts, evidence supports individualized use of parenteral beta2 agonists, magnesium sulfate, aminophylline, leukotriene inhibitors, or positive pressure mask ventilation before intubation. (+info)
Hypersensitivity and idiosyncratic reactions to oxaliplatin.
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BACKGROUND: Oxaliplatin is a third-generation platinum analog that is used to treat a variety of solid tumors, particularly colorectal carcinoma. Patients may develop hypersensitivity reactions, although this complication occurs infrequently. METHODS: Three patients developed hypersensitivity reactions to oxaliplatin while undergoing treatment on a Phase I trial of oxaliplatin and capecitabine. An Entrez PUBMED search was performed to identify other cases. RESULTS: Two patients experienced the abrupt onset of erythema alone or with pruritus during the 9th and 11th infusions of oxaliplatin, whereas the other patient developed fever and mild dyspnea a few hours after the 9th oxaliplatin infusion. All 3 patients were rechallenged successfully for at least 1 additional oxaliplatin infusion by using oral dexamethasone, 20 mg orally, 6 and 12 hours before the administration of oxaliplatin and by administering intravenously 125 mg of solumedrol, 50 mg of diphenhydramine, and 50 mg of cimetidine 30 minutes before oxaliplatin. The literature review suggests two distinct patterns of reactions: classic hypersensitivity (as experienced by the first two patients) and idiosyncratic reactions (as experienced by the third patient). CONCLUSIONS: Patients who develop mild to moderate hypersensitivity to oxaliplatin may be pretreated with steroids and antagonists of Type 1 and 2 histamine receptors, whereas patients who develop severe reactions are unlikely to tolerate further therapy. (+info)
Crescentic, proliferative IgA nephropathy: clinical and histological response to methylprednisolone and intravenous cyclophosphamide.
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BACKGROUND: IgA nephropathy is an immune-complex glomerulopathy that can result in capillary or extra-capillary proliferation. Previous attempts to correlate specific histological findings including cellular crescents or endocapillary proliferation, with clinical outcomes, have produced conflicting results. METHODS: We conducted a prospective open-labelled trial of 12 patients with crescentic, proliferative IgA nephropathy and clinically progressive disease and treated them with pulse steroids and intravenous cyclophosphamide. Therapy included pulse solumedrol at 15 mg/kg/day for 3 days, followed by monthly intravenous cyclophosphamide at 0.5 g/m(2) body surface area for 6 months. Clinically significant proteinuria (>1.0 g/24 h) was present in all patients, while nephrotic-range proteinuria (>3.0 g/24 h) was observed in eight of 12 patients. All patients were hypertensive (BP >140/90 mmHg). RESULTS: After 6 months of treatment, the mean serum creatinine was reduced from a maximum of 2.65+/-0.39 to 1.51+/-0.10 mg/dl (P<0.03), while proteinuria was reduced from 4.04 to 1.35 g/24 h (P<0.01). The mean slope of 1/serum creatinine increased from -0.0398+/-0.02 to 0.0076+/-0.01 after 6 months of therapy, but this trend did not reach statistical significance (P<0.08). A repeat kidney biopsy was performed in all treated patients. Endocapillary proliferation, cellular crescents and karyorrhexis were eliminated in all 12 patients after 6 months of therapy, while interstitial fibrosis and tubule dropout remained unchanged. To determine the long-term efficacy of the treatment, treated patients were compared to 12 historical controls matched for severity of IgA on initial biopsy. After 36 months, the rate of end-stage renal disease in the treated group was lower (1/12) than in the historical controls (5/12). CONCLUSIONS: We conclude that steroids and intravenous cyclophosphamide reduce proliferative lesions, reduce proteinuria and stabilize renal function in patients with crescentic IgA nephropathy. (+info)