Cyclophosphamide therapy as an adjunct in refractory post-tubercular arachnoiditis

IntroductionThere is no satisfactory treatment for post tubercular arachnoiditis (TB arachnoiditis). We did this study to investigate the efficacy and safety of cyclophosphamide as adjuvant therapy for post TB arachnoiditis refractory to corticosteroids and anti-tubercular therapy (ATT).MethodsThis was a retrospective case series of patients of refractory post TB arachnoiditis leading to paraparesis and vision loss who received cyclophosphamide as an adjuvant therapy along with standard ATT and corticosteroids. These patients were treated with intravenous cyclophosphamide (dose 500 mg/m²) once a month for 4 consecutive months after informed written consent and were assessed clinically and radiologically before and after cyclophosphamide therapy.ResultsWe had 4 patients with refractory post TB arachnoiditis of whom three became independently ambulatory. There was significant clinical as well as radiological improvement in all the patients.ConclusionsCyclophosphamide therapy could be an effective therapy for patients with refractory post TB arachnoiditis. Well-designed randomized controlled studies are essential to study the safety and efficacy of cyclophosphamide in this condition.     

Cyclophosphamide inhibits the development of diabetes in the diabetes-prone BB rat

Abstract Aims/hypothesis. Cyclophosphamide has been shown to augment the diabetic process in NOD mouse and BB rat models of Type I (insulin-dependent) diabetes mellitus. Because cyclophosphamide has, however, been shown to increase immunoregulatory cell activity, we examined if cyclophosphamide treatment increases immunoregulatory cell activity and inhibits the diabetic process in BB rats. Methods. The development of insulitis and diabetes was explored in BB rats treated with saline and cyclophosphamide (60 to 175 mg/kg body weight). Subsets of spleen cells were assessed by flow cytometry and cytokine gene expression by RT-PCR. To determine if cyclophosphamide induces immunoregulatory cell activity, the development of diabetes was assessed in BB rats injected with spleen cells from rats treated with saline and cyclophosphamide. Results. All dosages of cyclophosphamide decreased the development of diabetes. The degree of insulitis was lower in pancreata from 55-day-old rats treated with cyclophosphamide than those from controls. Cyclophosphamide caused no alterations in the numbers of NK cells, T-cell subsets, or RT6.1⁺ T cells. The adoptive transfer of spleen cells from cyclophosphamide-treated rats to BB rats inhibited the development of diabetes. Cyclophosphamide treatment decreased IL-12, IL-1β, IL-2, IFN-γ and TNF-α gene expressions in mononuclear spleen cells but IL-4 gene expression increased. Conclusion/interpretation. These findings show that cyclophosphamide treatment decreases the development of diabetes by inhibiting the development of insulitis. This inhibitory action of cyclophosphamide on the diabetic process seems to be mediated by the induction of immunoregulatory cell activity. The suppression of cytokines that promote Th1 cell differentiation by cyclophosphamide treatment could also play a part in the diabetes sparing effect of cyclophosphamide. [Diabetologia (2000) 43: 986–994] Received: 10 December 1999 and in revised form: 13 April 2000     

Different effects of cyclophosphamide in vivo and phosphamide mustard in vitro on two cell clones of chemically induced mammary carcinoma of the rat

Summary Two cell clones of a methylnitrosourea-induced rat mammary carcinoma, a hyperdiploid (44 chromosomes, clone A) and a hypertetraploid clone (88 chromosomes, clone B) were cultured and transplanted subcutaneously into three groups of eight rats. Group 1 was treated with 62.6 mg cyclophosphamide/kg, group 2 with 41.8 mg/kg once weekly for 3 weeks. The volume of tumors derived from clone B cells was diminished by the administration of the agent, whereas clone A cell tumors did not respond. Incubation of cells of both clones with phosphamide mustard in vitro showed that cells of clone B are much more sensitive to the activated cyclophosphamide, especially after incubation in low concentrations of 40 M and 20 M, than those of clone A. It is concluded that the initial success of cyclophosphamide therapy on chemically induced tumors is due to the different sensitivities of the tumor cell populations.     

Complete remission of refractory anemia following a single high dose of cyclophosphamide

 We describe a case of stable complete remission in a patient with refractory anemia complicated by severe autoimmune hemolytic anemia, achieved with a single high dose (4 g/m²) of cyclophosphamide (cyclo). Concomitantly, an effective mobilization of CD34-positive cells was induced. Other immunosuppressive approaches including high-dose methylprednisolone, high-dose immunoglobulin, and cyclosporine had been ineffective. This finding suggests that, in selected cases, an immunologic mechanism may mediate cytopenia in myelodysplastic syndromes (MDS). In addition, it demonstrates that successful mobilization of peripheral blood stem cells can be induced with high-dose cyclo in MDS. Received: September 14, 1998 / Accepted: October 9, 1998     

Churg‐Strauss syndrome with poor‐prognosis factors: A prospective multicenter trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in forty‐eight patients

Objective

To compare long and short durations of adjunctive cyclophosphamide for the treatment of severe Churg‐Strauss syndrome (CSS).

Methods

In this prospective multicenter therapeutic trial, 48 patients with CSS with at least 1 poor‐prognosis factor at baseline were treated with glucocorticoids and either 12 or 6 intravenous cyclophosphamide pulses.

Results

At 8 years, complete remission rates and severe side effects of therapy were comparable for both groups. The overall difference in relapses was not significant between the 12‐pulse and the 6‐pulse regimens (P = 0.07), but when considering only the number of mild relapses this difference became statistically significant (P < 0.02). Although the total number of inclusions was not reached, the study was stopped prematurely in response to the superiority of the 12‐pulse regimen.

Conclusion

We concluded that 12 cyclophosphamide pulses were better able to control severe CSS than a 6‐pulse regimen. The optimal duration of therapy remains to be determined.     

High-dose azathioprine pulse therapy as a new treatment option in patients with active Wegener’s granulomatosis and lupus nephritis refractory or intolerant to cyclophosphamide

The objective of this study was to evaluate the feasibility and safety of high-dose azathioprine pulse (HAP) therapy in the induction of remission in patients with active Wegeners granulomatosis (WG) or progressive lupus nephritis (LN) refractory to or intolerant of cyclophosphamide. Four patients with antineutrophil cytoplasmic antibody (ANCA)-associated WG and two patients with progressive LN were treated with HAP (1200–1800 mg) applied monthly as continuous intravenous infusions at 50 mg/h. Patients received a total of 50 courses of intravenous azathioprine (AZA) therapy. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS) and the Systemic Lupus Erythematosus Activity Index (SLEDAI). As only partial remission was induced in patients with progressive LN on this regimen, an additional 18 cycles were applied in these patients in which oral AZA at 100 mg/day in weeks 2 and 3 was added between two intravenous courses. A hereditary defect in thiopurine methyltransferase activity was excluded before initiation of treatment. High-dose azathioprine pulse and the intensified HAP treatment were well tolerated. Complete remission was achieved in two patients with WG suffering from three relapses of disease on application of 2–6 courses of HAP. Remission was maintained for 16–24 months. The remaining two patients with WG were withdrawn after 2–3 courses due to unchanged disease activity. In two patients with LN, partial remission was noted on 6–9 courses of HAP; however, the patients relapsed despite therapy with methotrexate and mycophenolate mofetil. The intensified HAP regimen led to partial or complete remission in both LN patients which was confirmed by sequential renal biopsies. Our results suggest that HAP therapy represents a well-tolerated regimen in patients with active WG and LN intolerant of or refractory to cyclophosphamide. As partial or complete remission was observed in four of six patients, further studies seem warranted to assess clinical efficacy in these patients.     

Strontium fructose 1, 6‐diphosphate alleviate cyclophosphamide‐induced oligozoospermia by improving antioxidant and inhibiting testicular apoptosis via FAS/FASL pathway

This study investigated the treatment effects of a new compound, strontium fructose 1, 6‐diphosphate (FDP‐Sr), in cyclophosphamide (CP)‐induced oligozoospermia. FDP‐Sr, with extra high‐energy supply, could reverse male hypogonadism in the testis. Male Wistar rats were randomly divided into three groups: control group (vehicle treated), CP group and CP + FDP‐Sr group. Both CP group and CP + FDP‐Sr groups were orally administered CP (20 mg kg^?1) consecutively for the first 7 days to establish CP‐induced testicular toxic models. Subsequently, CP group was given orally distilled water per day, whereas CP + FDP‐Sr group was received FDP‐Sr (200 mg kg^?1) for 49 days. Compared to the CP group, the FDP‐Sr group showed significantly increased levels of serum testosterone, testis relative weights and epididymal sperm counts in rats. In addition, rats treated by FDP‐Sr showed the recuperative activities of testicular marker enzymes and normalised levels of antioxidants in tissue. Testicular protection of FDP‐Sr was further demonstrated by enhancing expression of P450scc, reducing ability of FAS/FASL and generating cytoprotection in the histopathological study. FDP‐Sr appeared to possess an ability to attenuate CP‐induced reproduction toxicity via the activation of antioxidants and steroidogenesis enzymes, and alleviate oligozoospermia via inhibition of testicular apoptosis by FAS/FASL pathway.     

Does Cyclophosphamide Play a Protective Role Against Neuronal Loss in Chronic <Emphasis Type="Italic">T.</Emphasis><Emphasis Type="Italic"> cruzi</Emphasis> Infection?

In this study, we verified the possible role of cyclophosphamide (CY) in protecting or not against neuronal losses in young and aged male Calomys callosus chronically infected with the MORC-1 strain of Trypanosoma cruzi through numerical quantification of neurons from the myenteric plexus of the colon and quantification of nitric-oxide concentration (NO) during the acute and chronic phase of infection. For this purpose, groups of young C. callosus were infected with the MORC-1 strain of T. cruzi. A group of infected animals received i.p. 0.2 mg/ml genuxal dissolved in distilled water treatment with CY. NO concentration in aged animals displayed reduced levels when compared to those found in young animals. No significant alterations in the number of neurons were observed in young animals, but for aged ones, a protective role of CY in reducing neuron loss was noted, in addition to enhancing the neuronal volume, area, and perimeter. These results suggest that CY administration, depending on the dose and time span, can act as a protective agent against neuronal losses.     

Human regulatory T cells lack the cyclophosphamide‐extruding transporter ABCB1 and are more susceptible to cyclophosphamide‐induced apoptosis

ATP‐binding cassette (ABC) transporters, including ABC‐transporter B1 (ABCB1), extrude drugs, metabolites, and other compounds (such as mitotracker green (MTG)) from cells. Susceptibility of CD4⁺ regulatory T (Treg) cells to the ABCB1‐substrate cyclophosphamide (CPA) has been reported. Here, we characterized ABCB1 expression and function in human CD4⁺ T‐cell subsets. Naïve, central memory, and effector‐memory CD4⁺ T cells, but not Treg cells, effluxed MTG in an ABCB1‐dependent manner. In line with this, ABCB1 mRNA and protein was expressed by nonregulatory CD4⁺ T‐cell subsets, but not Treg cells. In vitro, the ABCB1‐substrate CPA was cytotoxic for Treg cells at a 100‐fold lower dose than for nonregulatory counterparts, and, inversely, verapamil, an inhibitor of ABC transporters, increased CPA‐toxicity in nonregulatory CD4⁺ T cells but not Treg cells. Thus, Treg cells lack expression of ABCB1, rendering them selectively susceptible to CPA. Our findings provide mechanistic support for therapeutic strategies using CPA to boost anti‐tumor immunity by selectively depleting Treg cells.     

曲普瑞林预防环磷酰胺对系统性红斑狼疮患者卵巢储备功能医源性损害的临床比较研究

目的:探讨促性腺释放激素类似物(GnRHa)曲普瑞林联合环磷酰胺(CTX)治疗系统性红斑狼疮(SLE)对SLE患者的卵巢储备功能的短期保护作用,初步评价GnRHa作为CTX治疗SLE的卵巢保护剂的有效性。方法:选取2013年3月至2015年3月在北京大学深圳医院风湿免疫科确诊为SLE的育龄女性27例,患者初次使用CTX且治疗周期为6个月。根据患者是否使用GnRHa分为CTX+GnRHa组(12例)和CTX组(15例)。ELISA法测定AMH值。比较两组SLE患者治疗前后AMH变化及两组间AMH差异。结果:CTX+GnRHa组、CTX组患者的治疗前AMH值分别为2.42±0.85和2.39±0.88,差异无统计学意义(P=0.935);治疗后AMH值分别为1.99±0.56和1.31±0.48,差异有统计学意义(P=0.002)。CTX+GnRHa组的治疗前后AMH值比较,差异无统计学意义(P=0.162)。CTX组的治疗前后AMH值比较,差异有统计学意义(P0.000)。结论:GnRHa辅助CTX治疗SLE对患者卵巢储备功能有一定保护作用。