Disseminated eruptive granuloma annulare induced by levetiracetam

Granuloma annulare (GA) is a benign, granulomatous cutaneous disease without clear etiology. Disseminated and drug induced granuloma annulare is a rare presentation. We present a 47-year-old woman with diffuse circular erythematous eruptions following treatment with levetiracetam. Her clinical and histopathological findings were compatible with the diagnosis of granuloma annulare. To the best of our knowledge, there is no previous report of this skin disease as a result of levetiracetam use. We report this case to highlight this antiepileptic drug as a possible etiologic agent in disseminated granuloma annulare.     

Treatment of recalcitrant generalized granuloma annulare with adalimumab

Granuloma annulare is a benign, usually self-limited, dermatosis of unknown cause. Generalized lesions occur in approximately 15 percent of patients with GA and may cause mild to severe cosmetic disfigurement. The treatment of generalized granuloma annulare can be challenging. We report the case of a 36-year-old male patient with a generalized granuloma annulare who had failed topical and systemic glucocorticoids, systemic retinoids, dapsone, minocycline, PUVA therapy, and hydroxicloroquine and was successfully treated with adalimumab, an anti-TNF-α monoclonal antibody. Adalimumab may be an additional option in the treatment of recalcitrant forms of granuloma annulare.     

Generalized granuloma annulare in a patient with adult onset diabetes mellitus

Granuloma annulare is a benign idiopathic disorder, which affects the dermis. Several reports have demonstrated an association between granuloma annulare and diabetes mellitus. We report the case of a 69-year-old man with an unusual presentation of generalized granuloma annulare following the diagnosis of adult onset diabetes mellitus.     

播散型环状肉芽肿四例临床病理特点与治疗研究及文献回顾

目的探讨播散型环状肉芽肿（GGA）的临床表现、组织病理特征、治疗方法及预后。方法对4例GGA的临床表现、组织病理改变、治疗方法及预后进行回顾性研究,并对近年GGA的国内外文献进行了回顾。结果4例患者,男女各2例,年龄42～72岁,以全身丘疹为主诉就诊。病程3个月至1年不等。3例曾误诊。4例GGA表现为躯干、四肢及颈部泛发肤色或红色丘疹、斑丘疹,部分损害中央可见脐凹,边缘呈环状。3例组织病理检查均示真皮浅中层胶原黏液变性,周围淋巴细胞、组织细胞呈栅状排列。1例示真皮浅中层胶原排列紊乱,胶原轻度变性,胶原束间可见散在分布的淋巴细胞、组织细胞及少量多核巨细胞。4例患者均接受了糖皮质激素制剂局部治疗,系统治疗分别为抗组胺药物、糖皮质激素、羟氯喹、异维A酸及补骨脂素紫外线疗法治疗。患者治疗后根据用药及患者治疗反应情况,不定期随诊。根据皮损数量和瘙痒程度变化判断疗效。随访6～35个月,平均随访（26±14）个月。2例患者治愈,随访2年无复发,1例有效,1例无效。结论GGA相对少见,容易误诊,临床需要注意寻找脐凹样或环状损害改变的特征性表现。组织病理特征为栅状肉芽肿或弥漫性淋巴组织细胞浸润伴胶原变性。 糖皮质激素、羟氯喹治疗及光化学疗法治疗有一定疗效。     

Etanercept therapy for silicone granuloma

A patient developed a typical, painful, and debilitating reaction on the thighs following injection of ostensibly medical grade "silicone" to achieve alteration of body contours. The refractory silicone granuloma responded dramatically to treatment with etanercept.     

A network meta-analysis of the efficacy of belatacept,cyclosporine and tacrolimus for immunosuppression therapy in adult renal transplant recipients

Belatacept is a first in-class co-stimulation blocker developed for primary maintenance immunosuppression following renal transplantation. The objective of this study was to estimate the efficacy of belatacept relative to tacrolimus and cyclosporine among adults receiving a single kidney transplant.

A systematic review was conducted of randomized clinical trials (RCTs) published between January 1990 and December 2013 using EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials, and unpublished study reports from two belatacept RCTs. Bayesian network meta-analysis (NMA) methods were used to compare the efficacy measures, mortality, graft loss, acute rejection and glomerular filtration rate (GFR). Heterogeneity was quantified using statistical metrics and potential sources were evaluated using meta-regression and subgroup analysis.

A total of 28 RCTs comparing tacrolimus with cyclosporine, and three comparing belatacept with cyclosporine, were identified.

All three agents provided comparable graft and patient survival, despite a higher risk of acute rejection associated with belatacept and cyclosporine. Belatacept was associated with significant improvement in GFR versus cyclosporine. Compared with tacrolimus, this difference was clinically meaningful yet statistically non-significant. The probability of being the best treatment was highest for belatacept for graft survival (68%), patient survival (97%) and renal function (89%), and highest for tacrolimus for acute rejection (99%).Variability in donor, recipient, and trial characteristics was present in the included RCTs; however, minimal statistical heterogeneity was detected in the analysis of acute rejection, graft or patient survival, and none of the characteristics were found to be significantly associated with relative effect. Although the direction of effect of immunosuppressants on GFR was consistent across RCTs, precise estimation of its magnitude was limited by a small number of RCTs and heterogeneity in relative effect sizes.

Clinicians often seek an alternative to CNIs due to their nephrotoxic effects. The results of this indirect comparison indicate that belatacept is an effective immunosuppressive agent in renal transplantation among adults.     

Therapeutic efficacy of DL-alpha-lipoic acid on cyclosporine A induced renal alterations

The present study was designed to evaluate the possible beneficial effect of lipoic acid in preventing the renal damage induced by cyclosporine A in rats. Male albino rats of Wistar strain were divided into four groups and treated as follows. Two groups received cyclosporine A by oral gavage (25 mg/kg/body weight) for 21 days to induce nephrotoxicity, one of which simultaneously received lipoic acid treatment (20 mg/kg body weight) for 21 days. A vehicle (olive oil) and a lipoic acid drug control were also included. Cyclosporine A induced renal damage was evident from the decreased activities of tissue marker enzymes (alkaline phosphatase, acid phosphatase, lactate dehydrogenase, aspartate transaminase and alanine transaminase) and decreased activities of ATPases (Na+, K+-ATPase, Ca2+-ATPase and Mg2+ ATPase). An apparent increase in the levels of serum constituents (urea, uric acid and creatinine) and urinary marker enzymes (N-acetyl-beta-D-glucosaminidase, beta-glucosidase, beta-galactosidase, cathepsin-D and gamma-glutamyl transpeptidase) along with significant decline in creatinine clearance were seen in the cyclosporine treated rats, which was reversed upon treatment with lipoic acid. Ultrastructural observations were also in agreement with the above abnormal changes. Lipoic acid effectively reverted these abnormal biochemical changes and minimized the morphological lesions in renal tissue. Hence, this study clearly exemplifies that lipoic acid might be an ideal choice against cyclosporine A induced cellular abnormalities.     

Area under the curve monitoring of cyclosporine therapy: the early posttransplant period

The impact of a new monitoring strategy on whole blood concentrations of cyclosporine measured by a specific monoclonal radioimmunoassay was investigated in a group of 37 renal transplant patients. Before transplantation, the patients received a standard intravenous (i.v.) and oral (p.o.) test dose of cyclosporine to calculate their individual i.v. and p.o. starting dose rates to achieve a certain target steady-state cyclosporine concentration. After transplantation, the designated i.v. dose rate was continuously infused for 2 days, at which time the steady-state concentration was measured. Then, the designated oral dose for 24 h was administered while the infusion was continued at an unaltered rate. The oral absorption of cyclosporine was documented by blood samples over the following 8 h. If necessary, this overlap of i.v. and p.o. dosing was repeated until blood concentrations of cyclosporine rose at least 700 ng/ml over the steady-state concentration. By that time, the infusion was stopped and oral dosing continued. Individualized infusions led to steady-state concentrations within a range that did not exceed 1.1 times the median concentration of 472 ng/ml. Standard infusion rates in the past produced a much wider range of steady-state concentrations (9.6 times the median). Individualized infusions reached the target steady-state concentration with a significant positive bias of 17% (SEM = +/- 32%, range of -36 to +105%). Individualized oral doses reached the target average steady-state concentration (calculated by dividing the area under the concentration-time curve by the dosing interval) with an inferior precision (median = 2.6%, range of -54 to +130%) but without a positive or negative bias.(ABSTRACT TRUNCATED AT 250 WORDS)     

环孢素A治疗难治性特发性血小板减性紫癜疗效观察

目的探讨环孢素A治疗难治性特发性血小板减少性紫癜的疗效、毒副反应和患者对药物的耐受性。方法19例难治性特发性血小板减少性紫癜患者口服环孢素A,剂量为3mg·kg-1·d-1。定期复查血常规、肝肾功能,并观察药物的副作用。结果良效14例(73.7%),显效4例(21.1%),无效1例(5.2%)。使用环孢菌素后18～74天(43.7±13.5天)血小板计数开始上升。14例良效患者血小板升为正常的时间为36～105天(68.6±19.4天),4例显效患者血小板达到最高的时间为57～95天(71±17.3天)。3例良效患者停药后复发,复用环孢素A仍然有效。复发患者及3例显效患者用小剂量环孢素A维持。部分患者出现轻微副反应。结论环孢素A治疗难治性特发性血小板减少性紫癜效果良好,毒副反应轻微,患者耐受性好。     

Two-hour cyclosporine concentration determination: an appropriate tool to monitor neoral therapy?

Cyclosporine is a critical dose drug for which individualisation by therapeutic drug monitoring is indisputable. Current evidence suggests that a single concentration (C2) taken two hours after cyclosporine administration with the microemulsion formulation better predicts exposure and events than the trough concentration (C(0)), which is routinely used for adjusting the dosage of this drug. Studies have shown that the greatest calcineurin inhibition and the maximum inhibition of IL-2 production occur in the first 1 to 2 hours after dosing. These findings support the concept that the C2 level better reflects immunosuppressive efficacy than the trough concentration. Preliminary data from an outcome study in liver transplant recipients have shown that the incidence of biopsy proven moderate to severe acute rejection was significantly lower in patients managed by C2 monitoring compared with those monitored by C(0). The critical importance of achieving adequate cyclosporine exposure during the first 3 to 5 posttransplant days to prevent acute rejection has been documented in prospective studies with de novo renal and liver transplant recipients. Conversion of maintenance liver and heart transplant patients to C2 monitoring resulted in an amelioration of renal function. Time-dependent target values have been proposed for liver and renal transplant recipients. These require further prospective validation. For routine monitoring of C2 levels on-site validated dilution guidelines are necessary for most of the available immunoassays. C2 monitoring necessitates further organizational requirements which may be judged differently between transplant centers. In particular during the early posttransplant period C2 monitoring is a promising new option to make immunosuppressive therapy with the microemulsion formulation of cyclosporine safer and more efficient.     

Antidepressants: Their efficacy and place in therapy

This paper reviews and relates to the wider published literature a series of studies directed to the broad question of which antidepressant treatment is required for which kind of depressed patient. Adequate methodology requires comparisons with placebo and other active drugs, rather than analysis of single treatment groups, so that the magnitude of therapeutic benefit due to specific drug effects can be measured. Reasonably firm conclusions are now possible. Electroconvulsive therapy (ECT) is most effective in severely depressed patients, particularly those with delusions or retardation, and is superior to antidepressant drugs in such patients. Monoamine oxidase (MAO) inhibitors show some selectivity towards patients with anxiety or reversed functional shift symptoms, but this selectivity appears quite limited, and tricyclic antidepressants also benefit such patients. The possibility of other factors, not well reflected in clinical features, which determine consistency of response requires further investigation. Recent evidence has led to re-evaluation of the earlier view that tricyclic antidepressants were specifically indicated in endogenous depressions. They appear to be broad-spectrum antidepressants, with efficacy extending more widely into neurotic disorders, mixed anxiety depressions, anxiety disorders, and into the relatively mild non-endogenous depressions of general practice.     

免疫抑制药环孢素治疗药物监测中的实际问题

由于环孢素的口服生物利用度和药代动力学在不同个体间的明显差异,以及个体对环孢素敏感性和耐受性的差异,因此环孢素是临床上常规监测其血药浓度的药物。环孢素的治疗药物监测对于减少排异反应和毒性反应的发生,提高移植物的存活率和患者的生存率,具有重要的临床意义。环孢素体内过程复杂,个体差异大,血浓度测定结果的影响因素多。临床实践中需要对影响环孢素药动学、药效学以及血药浓度测定所用的仪器、方法和标本采集时间等诸多因素予以综合全面的考虑,确定适合个体病人的最佳给药剂量,以实现真正的合理用药。     

液氮冷冻和外用卤米松乳膏治疗局限性环状肉芽肿临床对比观察

目的对比观察液氮冷冻和外用卤米松乳膏治疗局限性环状肉芽肿的疗效、安全性及美容效果。方法选择局限性环状肉芽肿患者60例,随机分成2组。观察组用液氮冷冻治疗1³次,对照组皮损外用卤米松乳膏2周停用1周。治疗后第1、5个月,分别比较临床疗效、安全性及美容效果。结果治疗1个月后,观察组、对照组的有效率分别为83.33%、20.0%,两组比较差异有统计学意义(P<0.01);治疗5个月后,观察组的有效率为100%,美容满意度为86.67%,对照组分别为43.33%、40.0%,两组比较差异有统计学意义(P<0.05)。结论液氮冷冻治疗局限性环状肉芽肿较外用卤米松乳膏临床疗效更显著,美容满意度更高,是一种简单、安全、有效的治疗方法。     

Rebound of rat carrageenin granuloma following cessation of anti-inflammatory steroid therapy

Glucocorticoid therapy induced rapid involution of chronic granulomatous inflammation in rats by subcutaneous injection of carrageenin. Hydrocortisone acetate injected into the granuloma pouch at doses higher than 3 mg/kg/day for 3 days caused maximum involution. After withdrawal of the corticoid therapy, rebound of the granulomatous inflammation took place resulting in rapid recovery of the wet weight and total content of tissue DNA and non-collagen proteins. A dose of 3 mg/kg/day was optimal for observing this rebound phenomenon. In order to investigate metabolic aspects of the rebound phenomenon minced granuloma was incubated in vitro with [³H] thymidine or [³H] proline. The rate of incorporation of the labeled precursor into non-collagen protein was elevated near to the normal level by 24 hr after the interruption of the corticoid treatment. A second step in the course of the recovery was a rapid increase in the incorporation of labeled thymidine into DNA which was attained by 48 hr after the last injection of the corticoid. The rate of recovery of the total amount of non-collagen protein, however, was rather slow compared with that of DNA which reached the control level 3 days after the withdrawal of the corticoid therapy. The total non-collagen protein of the granuloma reached almost complete recovery 1 day later. These results suggest that the synthesis of some fractions of the granuloma proteins which involve proteins essential for DNA synthesis was activated before the reactivation of the synthesis of DNA and some other proteins. Recovery of collagen synthesis was not complete until 4 days after the cessation of the corticoid treatment. Consequently, the total amount of collagen was still lower than that of the control on the last day of the experiment.     

Area-under-the-curve monitoring of cyclosporine therapy: performance of different assay methods and their target concentrations

The measurement of areas under the concentration-time curve (AUC) was recently introduced as an alternative to trough level monitoring of cyclosporine therapy. The AUC is divided by the oral dosing interval to calculate an average concentration. All measurements are performed at clinical steady state. The initial evaluation of AUC monitoring showed advantages over trough level monitoring with concentrations of cyclosporine measured in serum by the polyclonal radioimmunoassay of Sandoz. This assay technique is no longer available and the following assays were performed in parallel during up to 173 AUC determinations in 51 consecutive renal transplant patients: polyclonal fluorescence polarization immunoassay of Abbott in serum, specific and nonspecific monoclonal radioimmunoassays using 3H and 125I tracers in serum and whole blood, and high performance liquid chromatography in whole blood. Both trough levels and average concentrations at steady state measured by those different techniques were significantly correlated with the oral dose. The best correlation (r2 = 0.54) was shown by average concentrations measured in whole blood by the specific monoclonal radioimmunoassay of Sandoz (3H tracer). This monitoring technique was also associated with the smallest absolute error between repeated observations in the same patient while the oral dose rate remained the same or was changed. Both allegedly specific monoclonal radioimmunoassays (with 3H and 125I tracer) measured significantly higher concentrations than the liquid chromatography. (ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term safety and efficacy of topical cyclosporine in 156 children with vernal keratoconjunctivitis

Vernal keratoconjunctivitis (VKC) is a chronic and potentially sight-threatening disease. Topical corticosteroids (Cs) seem to be the only effective treatment for this condition, although severe side effects may occur owing to their prolonged use. More recently, cyclosporine (Cyc) eye drops have been reported as a valid alternative, but so far such treatment has only been successfully experimented for a short time and in small numbers of patients. The aim of our study is to evaluate the long term safety and efficacy of topical cyclosporine eye drops in children suffering from VKC. Over a period of 7 years we followed a large group of children suffering from severe VKC. They were selected to start cyclosporine eye drop treatment, because of the prompt relapse of their disease as soon as they stopped topical corticosteroids administration. All patients were followed-up in an ambulatory care assessment. A total of 156 children with VKC were treated with topical cyclosporine eye drops over a period ranging from two to seven years [mean time 3.8 +/- 1.09 years] during the seasonal relapse [range 9-66 months; mean time 24.7+/-10.4 months]. Two formulations, at 1% and 2% (82% and 18%, respectively) concentrations, of cyclosporine eye drops were made. The dosage administered was one drop in each eye from two to four times a day, depending on the severity of the disease and the season. The ocular objective scores were determined and compared every year, at the beginning and at the end of each treatment period. Blood samples were collected once a year in order to check both kidney and liver functions, as well as cyclosporine serum levels. We enrolled 156 patients (mean age 8.31+/-2.79 years; 116 males and 40 females) who were followed-up over a period of 7 years [156 (100%) children during the first and the second year; 138 (88.5%) patients until the third year; 90 (57.7%) until the fourth year; 32 (20.5%) until the fifth year; 10 (6.4%) until the sixth year and 2 (1.3%) until the seventh year]. The ocular objective scores significantly improved (p less than 0.001) over the years when comparing them at the beginning and the end of each seasonal treatment period, except for the last year. Over the treatment period, non-significant changes were recorded in terms of kidney and liver enzymatic activities and also in terms of cyclosporine serum levels. Cyclosporine eye drops, either at 1% or 2% concentrations, resulted safe and effective for long-term treatment of VKC in 156 children. The lack of significance of the score results during the seventh year can be explained by the small number of subjects treated for such a long period. A systematic ocular examination and both liver and kidney functional investigations allowed us to exclude the possibility of local or systemic side effects due to cyclosporine. If either transient or long-lasting, the occurrence of burning was referred by some of the patients treated, but none of them required to discontinue the drug. In conclusion, this is the first study showing that topical cyclosporine is easily handled even by children, with safe and effective results even when it is used over a long period of time. Our findings, though encouraging, need to be confirmed by further studies.     

Advantages of triple therapy with mizoribine, cyclosporine and prednisolone over other types of triple and/or double therapy including cyclosporine for renal transplantation.

Mizoribine (Mz) is an analogue of azathioprine (Az) with less hepatotoxicity, being extensively used as immunosuppressant in place of the latter agent especially in Japan. However, careful comparative studies of mizoribine (Mz), cyclosporine (Cy), and prednisolone (Pr) versus azathioprine (Az), Cy and Pr or Cy and Pr in renal allotranspalnt patients have not been reported. Retrospectively we compared triple therapy with Mz, Cy, and Pr (group I, n = 50) to triple therapy with Az, Cy and Pr (group II, n = 13) and/or double therapy with Cy and Pr (group III, n = 11) in one-haplotype-identical living related renal transplantations performed between Oct. 1984 through March 1989. Initial and maintenance doses of Cy in groups I and II were largely two thirds of those in group III. Patient and graft survival rates at 3 years in each group are 100% and 92% (group I), 100% and 91% (group II), and 91% and 82% (group III). There were no statistical differences in patient and graft survival rates between these three groups. The incidences of miscellaneous complications were the same in the groups. Bone marrow suppression, however, was significantly less in group I than in group II (P less than 0.005). Cy related nephrotoxicity was apparently less in groups I and II than in group III. Estimated US $5,000 in a year can be saved by immunosuppressive treatment in a patient of group I as compared to a patient in group III. Therefore, we conclude that triple therapy with Mz, Cy and Pr is superior to those with Az, Cy and Pr, and/or double therapy with Cy and Pr.