EGb761诱导血红素加氧酶-1在肺缺血再灌注损伤中的抗凋亡作用

目的 探讨银杏叶提取物EGb761诱导血红素加氧酶-1(HO-1)在肺缺血再灌注损伤中的抗凋亡作用.方法 40只健康SD大鼠随机分为4组:对照组(Sham组,不阻断右肺门)、缺血/再灌注组(I/R组,阻断右肺门30 min再灌注2 h),EGb761组(术前给予EGb761腹腔注射)、锌原卟啉组(Znppix组,术前给予EGb761及术中给予HO-1抑制剂Znppix干预).采用蛋白免疫印迹法(Western blot)检测肺组织HO-1蛋白、磷酸化JNK蛋白及Bcl-2蛋白表达;DNA原位末端标记(TUNEL)法测定肺组织细胞凋亡指数.结果 EGb761组HO-1表达灰度比值较I/R组与Sham组均升高(3.257±0.432 vs 1.329±0.310、0.187±0.101,P<0.05).磷酸化JNK1、磷酸化JNK2、Bcl-2蛋白表达灰度比值与细胞凋亡指数在I/R组、EGb761组、Znppix组分别为1.897±0.354、1.674±0.273、0.420±0.093与(14.91±0.49)%,0.681±0.131、0.715±0.116、1.384±0.190与(7.48±0.72)%,1.031±0.201、0.965±0.167、0.621±0.114与(9.01 =0.65)%.与I/R组比较,EGb761组磷酸化JNK蛋白表达下降,Bcl-2蛋白表达增加,细胞凋亡指数下降(P值均<0.05).与EGb761组比较,Znppix组磷酸化JNK蛋白表达增高,Bcl-2蛋白表达下降,细胞凋亡指数增高(P值均<0.05).结论 银杏叶提取物EGb761可诱导HO-1表达,进一步通过抑制JNK蛋白激酶活性及促进Bcl-2表达而在肺缺血再灌注损伤中发挥抗凋亡作用.     

Graves' disease induced by Na(131)I therapy for toxic multinodular goitre

A 59-year-old woman developed manifestations of Graves' disease several months after treatment with radioiodine (Na(131)) for toxic multinodular goitre. During subsequent treatment with additional radioiodine therapy Graves' ophthalmopathy developed which was severe and required treatment with prednisone and orbital radiotherapy. The literature on development of Graves' disease following Na(131) therapy is reviewed and possible pathophysiological mechanisms are discussed. In this case, possibly the first radioiodine therapy has illicited Graves' thyrotoxicosis and the subsequently added radioiodine treatments for the persistent Graves' thyrotoxicosis led to serious ophthalmopathy. Physicians should recognise Graves-like disease as a complication of Na(131)I therapy for toxic multinodular goitre and carefully consider the timing of consecutive radioiodine therapy.     

Influence of a 7-day treatment with Ginkgo biloba special extract EGb 761 on bleeding time and coagulation: a randomized, placebo-controlled, double-blind study in healthy volunteers.

During recent years, several case reports have been published in which the authors have voiced their suspicion of a causal relationship between hemorrhagic complications and the intake of Ginkgo biloba preparations. Therefore, a trial was conducted to investigate the influence of Ginkgo biloba special extract EGb 761 on hemostasiological parameters. Fifty healthy, male volunteers underwent 7 days of crossover treatment with 2 x 120 mg/day EGb 761 and placebo in randomized sequence. Between the two treatment phases, a washout-period of at least 3 weeks was inserted. The study's main outcome measures were bleeding time, coagulation parameters, platelet activity in response to various agonists and platelet morphology. The equivalence of the two treatments was analyzed by computing the 90% Fieller confidence intervals for the ratio between the means of the pre-post treatment differences for EGb 761 and placebo, respectively. Treatment safety was investigated by clinical laboratory and vital signs assessment and by adverse events monitoring. Among the 29 coagulation and bleeding parameters assessed, none showed any evidence of an inhibition of blood coagulation and platelet aggregation through EGb 761. Furthermore, the study did not reveal any evidence to substantiate a causal relationship between the administration of EGb 761 and hemorrhagic complications. As regards treatment tolerability, there were no interpretable differences between EGb 761 and placebo except for a slight increase of gastrointestinal complaints during administration of the herbal extract.     

The effect of methimazole pretreatment on the efficacy of radioactive iodine therapy in Graves' hyperthyroidism: one-year follow-up of a prospective, randomized study

The effect of antithyroid drugs on the efficacy of radioiodine (131I) treatment is still controversial. This study evaluated the effect of methimazole pretreatment on the efficacy of 131I therapy in Graves' hyperthyroidism. Sixty-one untreated patients were randomly assigned to receive 131I alone (32 patients) or 131I plus pretreatment with methimazole (30 mg/d; 29 patients). 131I was administered 4 d after drug discontinuation. The calculated 131I dose was 200 microCi/g thyroid tissue as estimated by ultrasound, corrected by 24-h radioiodine uptake. Serum TSH, T4, and free T4 were measured 4 d before 131I therapy, on the day of treatment, and then monthly for 1 yr. Considering cure as euthyroidism or hypothyroidism, based on free T4 measurement, approximately 80% of patients from both groups were cured 3 months after beginning 131I treatment. After 1 yr the groups were similar in terms of persistent hyperthyroidism (15.6% vs. 13.8%), euthyroidism (28.1% vs. 31.0%), or hypothyroidism (56.3% vs. 55.2%). Relapsed patients presented larger thyroid volume (P = 0.002), higher 24-h radioiodine uptake (P = 0.022), and T3 levels (P = 0.002). Multiple logistic regression analysis identified T3 values as an independent predictor of therapy failure. In conclusion, pretreatment with methimazole had no effect on either the time required for cure or the 1-yr success rate of 131I therapy.     

Propylthiouracil before 131I therapy of hyperthyroid diseases: effect on cure rate evaluated by a randomized clinical trial

A randomized clinical trial was performed to clarify whether pretreatment with propylthiouracil (PTU) before radioiodine ((131)I) therapy influences the final outcome of this therapy, as has been indicated by retrospective studies. Untreated consecutive hyperthyroid patients with Graves' disease (n = 23) or a toxic nodular goiter (n = 57) were randomized to either PTU (+PTU; n = 39) or no pretreatment (-PTU; n = 41) before compensated (131)I therapy. The median PTU dose was 100 mg, which was discontinued 4 d before treatment. The median (131)I activity was 302 MBq (range, 87-600 MBq). After (131)I therapy, the serum free T(4) index increased in the +PTU group from 97.7 +/- 47.5(+/-sd) nmol/liter at the time of therapy to 152.3 +/- 77.6 nmol/liter at 3 wk (P < 0.001) and 140.4 +/- 75.9 nmol/liter at 6 wk (P < 0.001). In the -PTU group, the serum free T(4) index, which was initially 254.3 +/- 145.7 nmol/liter, decreased significantly to 212.0 +/- 113.0 nmol/liter at 3 wk (P < 0.05) and 165.8 +/- 110.0 nmol/liter at 6 wk (P < 0.005). After 1 yr of follow-up, the treatment failure rate in patients with a toxic nodular goiter was four times higher in the +PTU group than in the -PTU group (nine of 20 vs. three of 25 patients; P = 0.06), whereas the difference among patients with Graves' disease was less obvious (four of six vs. four of nine; P = 0.81). Patients in the +PTU group who were cured had higher serum TSH (s-TSH) levels at the time of (131)I therapy than those who were not cured. By adjusting for a possible interfactorial relationship through a regression analysis, including the s-TSH level and type of disease, only PTU pretreatment had a significant adverse effect on the cure rate (P = 0.03). In conclusion, this randomized trial demonstrates that PTU pretreatment reduces the cure rate of (131)I therapy in hyperthyroid diseases, although this adverse effect seems to be attenuated by the concomitant rise in s-TSH.     

Ginkgo biloba extracts inhibit post-ischemic LTP through attenuating EPSCs in rat hippocampus

Ginkgo biloba extract 761 (EGb761), a standardized extract from the Ginkgo biloba leaf, is purported to inhibit NMDA receptor-mediated neuronal excitotoxicity and protect neurons form ischemic injury. However, the specific signal pathway involved in the effects of EGb761 on synaptic plasticity is still in dispute. In this article, effects of EGb761 and its monomer component ginkgolide A (GA), ginkgolide B (GB), ginkgolide C (GC) and quercetin on rat hippocampal synaptic plasticity were studied. The evoked Excitatory postsynaptic currents (EPSCs) and miniature EPSCs were recorded on hippocampal slices from SD rats (14–21 days of age) by whole-cell patch-clamp recording and long-term potentiation (LTP) was induced by theta-burst stimulation. Acutely applied EGb761 inhibited the LTP, but bilaterally affect the evoked EPSCs. The evoked EPSCs were increased by incubation of lower concentration of EGb761, then the evoked EPSCs were decreased by incubation of higher concentration of EGb761. EGb761 monomer component GA, GB and GC could also inhibit the TBS-induced LTP and EPSC amplitude but not paired-pulse ratio (PPR). But quercetin, another monomer component of EGb761, led to increase in EPSC amplitude and decrease in PPR. Simultaneously, EGb761 and its monomer component ginkgolides inhibited the post-ischemic LTP (i-LTP) by inhibiting the EPSCs and the AMPA receptor subunit GluA1 expression on postsynaptic membrane. The results indicated that high concentration of EGb761 might inhibit LTP and i-LTP through inhibition effects of GA, GB and GC on AMPA receptors.

     

Ginkgo biloba extract （EGb 761） attenuates lung injury induced by intestinal ischemia/reperfusion in rats： Roles of oxidative stress and nitric oxide

AIM： To investigate the effect of ginkgo biloba extract （EGb 761） on lung injury induced by intestinal ischemia/ reperfusion （ Ⅱ/R）. METHODS： The rat model of Ⅱ/R injury was produced by damping the superior mesenteric artery for 60 min followed by reperfusion for 180 min. The rats were randomly allocated into sham, Ⅱ/R, and EGb ＋Ⅱ/R groups. In EGb ＋Ⅱ/R group, EGb 761 （100 mg/kg per day） was given via a gastric tube for 7 consecutive days prior to surgery. Rats in Ⅱ/R and sham groups were treated with equal volumes of the vehicle of EGb 761. Lung injury was assessed by light microscopy, wet-todry lung weight ratio （W/D） and pulmonary permeability index （PPT）. The levels of malondialdehyde （MDA） and nitrite/nitrate （NO2/NO3）, as well as the activities of superoxide dismutase （SOD） and myeloperoxidase （MPO） were examined. Western blot was used to determine the expression of inducible nitric oxide synthase （iNOS）. RESULTS： EGb 761 markedly improved mean arterial pressure and attenuated lung injury, manifested by the improvement of histological changes and significant decreases of pulmonary W/D and PPT （P 〈 0.05 or 0.01）.Moreover, EGb 761 markedly increased SOD activity, reduced MDA levels and MPO activity, and suppressed NO generation accompanied by down-regulation of iNOS expression （P 〈 0.05 or 0.01）. CONCLUSION： The results indicate that EGb 761 has a protective effect on lung injury induced by Ⅱ /R, which may be related to its antioxidant property and suppressions of neutrophil accumulation and iNOS- induced NO generation. EGb 761 seems to be an effective therapeutic agent for critically ill patients with respiratory failure related to Ⅱ/R.     

Radioiodine treatment of hyperthyroidism-prognostic factors for outcome

There is little consensus regarding the most appropriate dose regimen for radioiodine (131I) in the treatment of hyperthyroidism. We audited 813 consecutive hyperthyroid patients treated with radioiodine to compare the efficacy of 2 fixed-dose regimens used within our center (185 megabequerels, 370 megabequerels) and to explore factors that may predict outcome. Patients were categorized into 3 diagnostic groups: Graves' disease, toxic nodular goiter, and hyperthyroidism of indeterminate etiology. Cure after a single dose of 131I was investigated and defined as euthyroid off all treatment for 6 months or T4 replacement for biochemical hypothyroidism in all groups. As expected, patients given a single dose of 370 megabequerels had a higher cure rate than those given 185 megabequerels, (84.6% vs. 66.6%, P < 0.0001) but an increase in hypothyroidism incidence at 1 yr (60.8% vs. 41.3%, P < 0.0001). There was no difference in cure rate between the groups with Graves' disease and those with toxic nodular goiter (69.5% vs. 71.4%; P, not significant), but Graves' patients had a higher incidence of hypothyroidism (54.5% vs. 31.7%, P < 0.0001). Males had a lower cure rate than females (67.6% vs. 76.7%, P = 0.02), whereas younger patients (<40 yr) had a lower cure rate than patients over 40 yr old (68.9% vs. 79.3%, P < 0.001). Patients with more severe hyperthyroidism (P < 0.0001) and with goiters of medium or large size (P < 0.0001) were less likely to be cured after a single dose of 131I. The use of antithyroid drugs, during a period 2 wk before or after 131I, resulted in a significant reduction in cure rate in patients given 185 megabequerels 131I (P < 0.01) but not 370 megabequerels. Logistic regression analysis showed dose, gender, goiters of medium or large size, and severity of hyperthyroidism to be significant independent prognostic factors for cure after a single dose of 131I. We have demonstrated that a single fixed dose of 370 megabequerels 131I is highly effective in curing toxic nodular hyperthyroidism as well as Graves' hyperthyroidism. Because male patients and those with more severe hyperthyroidism and medium or large-sized goiters are less likely to respond to a single dose of radioiodine, we suggest that the value of higher fixed initial doses of radioiodine should be evaluated in these patient categories with lower cure rates.     

Effects of Ginkgo biloba extract on cell proliferation and cytotoxicity in human hepatocellular carcinoma cells

AIM: To study the effect of Ginkgo biloba extract (EGb 761) containing 22-27% flavonoids (ginkgo-flavone glycosides) and 5-7% terpenoids (ginkgolides and bilobalides) on cell proliferation and cytotoxicity in human hepatocellular carcinoma (HCC) cells. METHODS: Human HCC cell lines (HepG2 and Hep3B) were incubated with various concentrations (0-1 000 mg/L) of EGb 761 solution. After 24 h incubation, cell proliferation and cytotoxicity were determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and lactate dehydrogenase (LDH) release, respectively. After 48 h incubation, the expression of proliferating cell nuclear antigen (PCNA) and p53 protein was measured by Western blotting. RESULTS: The results showed that EGb 761 (50-1 000 mg/L) significantly suppressed cell proliferation and increased LDH release (P<0.05) in HepG2 and Hep3B cells compared with the control group. The cell proliferation of HepG2 and Hep3B cells treated with EGb 761 (1 000 mg/L) was 45% and 39% of the control group (P<0.05), respectively. LDH release of HepG2 cells without and with EGb 761 (1 000 mg/L) treatment was 6.7% and 37.7%, respectively, and that of Hep3B cells without and with EGb 761 (1 000 mg/L) treatment was 7.2% and 40.3%, respectively. The expression of PCNA and p53 protein in HepG2 cells treated with EGb 761 (1 000 mg/L) was 85% and 174% of the control group, respectively. CONCLUSION: Ginkgo biloba extract significantly can suppress proliferation and increase cytotoxicity in HepG2 and Hep3B cells. Additionally, Ginkgo biloba extract can decrease PCNA and increase p53 expression in HepG2 cells.     

银杏叶提取物EGb761对局灶性脑缺血再灌注大鼠XIAP和Smac表达的影响

目的 探讨银杏叶提取物EGb761对局灶性脑缺血大鼠脑组织X-连锁凋亡蛋白抑制剂(X-linked inhibitor of apoptosis protein,XIAP)和Smac蛋白表达的影响.方法 40只雄性Wistar大鼠随机分为假手术组、脑缺血再灌注组、EGb761小剂量组和EGb761大剂量组,每组10只.制作大鼠大脑中动脉闭塞1.5 h再灌注24 h模型.EGb761小剂量组和EGb761大剂量绀于模型制作前1 h分别腹腔注射ECY0761 50 mg/kg和100 mg/kg.大鼠脑组织XIAP和Smac表达用免疫组化方法 检测.结果 EGb761小剂量绀和EGb761大剂量组脑组织XIAP表达分别为18.33±4.01和26.7±3.27,显著高于脑缺血再灌注绀的12.13±3.44(P均<0.01),且EGb761大剂量组高于EGb761小剂量组(P<0.01);EGb761小剂量组和EGb761大剂量组脑组织Smac表达分别为21.33±3.15和11.33±2.10,显著低于脑缺血再灌注组的28.93±4.96(P均<0.05),EGb761大剂最组显著低于EGb761小剂量组(P<0.01).结论 脑缺血再灌注可诱导XIAP和Smae表达,EGn761干预在上调XIAP表达的同时能抑制Smac蛋白表达,提高XIAP/Smac比值,可能是EGb761干预的保护机制之一.     

Ginkgo biloba extract EGb 761 attenuates myocardial stunning in the pig heart

Myocardial stunning, a transient contractile dysfunction that appears following a brief period of ischemia, is at least partly due to the production of oxygen-derived free radicals. The objective of the present study was to determine whether the Ginkgo biloba extract EGb761, which has antioxidant properties in vitro, can attenuate myocardial stunning in vivo. Forty-seven anesthetized open-chest farm pigs underwent 10 min of occlusion of the left anterior descending coronary artery (LAD), followed by 3 hours of reperfusion. They were pretreated with either physiological saline, 100 mg or 300 mg of EGb 761 (Protocol I) or 3 mg or 9 mg of ginkgolide B (GkB) (Protocol II). Contractile function was assessed by sonomicrometry. Both doses of EGb 761 significantly improved recovery of contractile function in the reperfused myocardium with segment shortening averaging 23 +/- 5 % of baseline values at 3 hours post-reflow in controls versus 81 +/- 10 % and 57 +/- 12 % in the EGb100 and EGb300 groups, respectively (p < 0.05 vs control in both cases). In contrast, neither dose of GkB improved functional recovery during reperfusion. ESR experiments revealed that EGb761 resulted in a 59 % decrease in myocardial spin-adduct release during reperfusion (p < 0.05 versus control and GkB groups). A significant 28 % decrease (p < 0.05 vs control group) was also obtained in GkB-treated animals. These results indicate that EGb 761 can attenuate myocardial stunning following a brief ischemic insult in the in situ pig heart by an effect that involves a decrease in the formation of free radicals. As the effect of EGb 761 on functional recovery cannot be explained by the presence of GkB, the beneficial action of the extract on myocardial stunning likely involves complementary effects of both its non-ginkgolide and ginkgolide constituents.     

Effects of extract from Ginkgo biloba on carbon tetrachloride-induced liver injury in rats

AIM: To study the effects of extract from Ginkgo biloba (EGb) containing 22% flavonoid and 5% terpenoid on chronic liver injury and liver fibrosis of rats induced by carbon tetrachloride (CCl4). METHODS: All rats were randomly divided into control group, CCl4-treated group, colchicine-treated group and EGb-protected group. Chronic liver injury was induced in experimental groups by subcutaneous injection of CCl4 and fed with chows premixed with 79.5% corn powder, 20% lard and 0.5% cholesterol (v/v). EGb-protected group was treated with EGb (0.5 g/kg body weight per day) for 7 wk. At the end of wk 8, all the rats were killed. Liver function, liver fibrosis, oxidative stress and expression of transforming growth factorβ1 (TGF-β1), a-smooth muscle actin (α-SMA) and typeⅠcollagens in liver were determined. In addition, pathology changes of liver tissue were observed under light microscope. RESULTS: The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and albumin (Alb) in EGb-protected group were notably improved as compared with the CCL4-treated group (P < 0.01). The contents of serum hyaluronic acid (HA), typeⅢprocollagen (PCⅢ), typeⅣcollagen (CIV) and the expression of hepatic tissue TGF-β1,α-SMA and typeⅠcollagen in EGb-protected group were significantly lower than those in CCL4-treated groups (P < 0.05, P < 0.01). The degrees of liver fibrosis in EGb-protected groups were lower than those in CCL4-treated groups (6.58±1.25 vs 9.52±2.06, P < 0.05). Compared to the CCL4-treated group, the levels of plasma glutathoine peroxidase (Se-GSH-Px), superoxide dismutase (SOD) and malondialdehyde (MDA) were strikingly improved also in EGb-protected group (P < 0.05, P < 0.01). CONCLUSION: EGb resists oxidative stress and thereby reduces chronic liver injury and liver fibrosis in rats with liver injury induced by CCl4     

Effect of iopanoic acid on radioiodine therapy of hyperthyroidism: long-term outcome of a randomized controlled trial

CONTEXT: Telepaque [iopanoic acid (IA)] is believed to rapidly ameliorate hyperthyroidism; however, it may preclude subsequent 131I therapy, possibly delaying it for several months. OBJECTIVE: Our objective was to see how early patients, made euthyroid with Telepaque, can be treated with 131I and to compare their short- and long-term outcome with patients treated with 131I, after making them euthyroid with carbimazole and beta-blockers. DESIGN: We conducted a randomized controlled trial. SETTING AND PATIENTS: We studied 200 hyperthyroid patients at a tertiary care teaching institute. INTERVENTIONS: The IA group received Telepaque, 500 mg/d orally, for 7 d and then no medication for 1 wk followed by 131I therapy if radioiodine neck uptake had recovered. The control group received 30-40 mg oral carbimazole daily until patients became euthyroid followed by 131I. MAIN OUTCOME: After 1 wk of Telepaque therapy and 6 wk of carbimazole, almost all patients became clinically and biochemically euthyroid, and 86 and 94% of patients were ready for 131I therapy after 1 and 2 wk off Telepaque, respectively. The cure rate, defined as euthyroid plus hypothyroid, after the first dose of 131I in controls and the IA group was 80 and 76.2%, respectively (P = 0.54). Thirty-two percent among controls and 25% in the IA group became hypothyroid within 1 yr (P = 0.33); thereafter, the annual rate of hypothyroidism was about 2% in both groups. After a mean follow-up duration of 11 yr, 58% of patients in the control group and 51% in the IA group were hypothyroid. CONCLUSIONS: Telepaque rapidly ameliorates hyperthyroidism without jeopardizing the subsequent radioiodine therapy, and the outcome of radioiodine therapy in this subset of patients is in no way different compared with those prepared by carbimazole.     

Propylthiouracil reduces the effectiveness of radioiodine treatment in hyperthyroid patients with Graves' disease.

In order to assess the effect of propylthiouracil (PTU) or methimazole (MMI) pretreatment on patient outcome after radioiodine therapy, we examined 100 patients with Graves' disease 3, 6, 9, and 12 months after administration of a 10-mCi standard single dose of 131I. They were assigned to one of three groups: no drug (ND) treatment (30 cases); MMI (45 cases); and PTU (25 cases). Antithyroid drugs (ATD) were withdrawn 15 days before radioiodine administration. The groups were similar concerning age, gender, ATD pretreatment duration, goiter size, and initial serum triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), antithyroid autoantibody levels, 24-hour radioiodine uptake and 131I dose administered per gram of thyroid tissue. ND and MMI groups presented a similar rate of cure of 73.3% and 77.8% respectively (p = NS). In contrast, the PTU group showed a rate of cure of only 32% (p < 0.05). Logistic regression analysis indicated that PTU administration (p = 0.003) and thyroid size (p = 0.02) were the variables related to radioiodine therapy failure. Our data demonstrate that the chance of 131I treatment failure is higher in individuals using PTU than in patients using MMI or not using any ATD before radioiodine (odds ratio [OR] 5.84; 95% confidence interval [CI] 1.82-18.76) suggesting that PTU should be avoided in the treatment of patients with Graves' disease.     

Success rate of radioiodine therapy in Graves' disease: the influence of thyrostatic medication

There is controversy whether simultaneous thyrostatic medication influences the outcome of radioiodine (131I) therapy in Graves' disease by reducing the absorbed energy dose of 131I when delivering a standard dose. We therefore sought to ascertain whether the outcome of ablative 131I therapy is in any way affected by simultaneous thyrostasis (carbimazole) by aiming for a constant absorbed dose of 200-250 Gy. We prospectively studied 207 patients with Graves' disease (106 with and 101 without simultaneous carbimazole at the time of 131I therapy). All patients were reexamined 3, 6, and 12 months after 131I therapy. The 101 nonthyrostatic patients showed a highly significantly greater success rate (93%) than the 106 thyrostatic patients (49%). Stepwise logistic regression demonstrated that failure was related to the administration of carbimazole during 131I therapy (P < 0.00005) and the absorbed dose (P < 0.025), but was not related to free T3, free T4, TSH receptor antibodies, or thyroid volume. The success rate was 100% in 93 nonthyrostatic patients with absorbed doses of 200 Gy or more, but was only 12.5% (1 of 8) for absorbed doses less than 200 Gy. Correlation between success and absorbed dose was significantly higher for nonthyrostatic than for thyrostatic patients (r = 0.93 vs. r = 0.24). Sixteen patients who discontinued thyrostasis 1-3 days before 131I therapy showed 94% successes. Simultaneous thyrostasis is the decisive factor against a successful 131I therapy even if the significantly reduced 131I uptake/half-life values under thyrostasis are compensated with a higher delivered dose to ensure a comparable absorbed dose, possibly due to the additionally effective radioprotective properties of carbimazole. Therefore, if clinically feasible, we recommend discontinuing thyrostasis at least 1 day before beginning 131I therapy, because even in hyperthyroid nonthyrostatic patients the success rate was 100%.     

Glucocorticoids do not influence the effect of radioiodine therapy in Graves' disease

OBJECTIVE: We evaluated, in a retrospective study, whether glucocorticoids given in order to avoid initiation or aggravation of ophthalmopathy during radioiodine (131I) therapy have an inadvertent effect on the final thyroid function. METHODS: Consecutive patients with Graves' disease (median age 50 years, range 21-82 years) treated with 131I therapy for the first time were included. Ninety-six patients (group 1) were given prednisolone (25 mg daily for 30 days beginning 2 days before 131I therapy) because of present or previous mild ophthalmopathy or the presence of risk factors (tobacco smoking and high concentrations of TSH-receptor antibodies) for developing this complication. One hundred and eleven patients received 131I therapy without prednisolone prophylaxis (group 2). RESULTS: The patients in group 1 were younger than those in group 2 (44.6+/-12.0 years versus 51.3+/-15.1 years; P = 0.001). At 1 year post therapy the patients were classified as hypothyroid, euthyroid or hyperthyroid. In group 1, the numbers of patients were 23, 35 and 38, respectively, while the corresponding numbers in group 2 were 26, 40 and 45, respectively (P = 0.99 between groups). The cure rate (attainment of euthyroidism or hypothyroidism) was 60% in group 1 and 59% in group 2 (P = 0.97). No significant between-group difference was found, neither in the median time-interval until development of hypothyroidism nor until recurrence of the hyperthyroid-ism. Using logistic regression the cure rate correlated negatively with age (P = 0.041) and the size of the thyroid gland (P = 0.010) and positively with serum TSH at treatment (P = 0.034), whereas no significant impact was found for the use of prednisolone, gender, smoking, presence of anti-thyroid peroxidase antibodies, use of anti-thyroid drugs or the presence of eye symptoms. CONCLUSIONS: Although glucocorticoids in some contexts seem to attenuate the radiation-induced oxidative stress this had no impact on the final outcome following 131I therapy of patients with Graves' disease.     

Stimulation with 0.3-mg recombinant human thyrotropin prior to iodine 131 therapy to improve the size reduction of benign nontoxic nodular goiter: a prospective randomized double-blind trial

BACKGROUND: Use of recombinant human thyrotropin increases the thyroid radioiodine (iodine 131 [(131)I]) uptake and may have a role in the context of (131)I therapy of benign goiter. METHODS: In a double-blind, placebo-controlled trial, 57 patients with nodular nontoxic goiter (51 women and 6 men) were randomized to receive either 0.3 mg of recombinant human thyrotropin (n = 28) or placebo (n = 29) 24 hours before (131)I therapy. The (131)I dose was calculated based on thyroid size (measured by ultrasound), thyroid (131)I uptake, and (131)I half-life. The follow-up period was 1 year and included measurements of thyroid size and function and patient satisfaction. RESULTS: Baseline median goiter volume was 51 mL (range, 20-99 mL) in the placebo group and 59 mL (range, 25-92 mL) in the thyrotropin group (P = .75). At 12 months, the mean +/- SEM relative goiter reduction was 46.1% +/- 4.0% in the placebo group and 62.1% +/- 3.0% in the thyrotropin group (P = .002 between groups). The difference was most pronounced among patients with large goiters. Within each group, there was no significant correlation between retained thyroid (131)I dose and goiter reduction. Adverse effects were significantly more frequent in the thyrotropin group (34 vs 12 events; P<.001). Permanent hypothyroidism developed in 3 patients (11%) in the placebo group compared with 16 patients (62%) in the thyrotropin group (P<.001). Patient satisfaction was high and uninfluenced by the use of recombinant human thyrotropin. CONCLUSIONS: Stimulation with recombinant human thyrotropin prior to (131)I therapy improves thyroid size reduction by 35%, with a 5-fold higher rate of hypothyroidism. These effects are, at least partially, mediated through mechanisms other than an increase in retained (131)I thyroid dose. Further recombinant human thyrotropin dose-finding studies are warranted before routine use.     

Continuous methimazole therapy and its effect on the cure rate of hyperthyroidism using radioactive iodine: an evaluation by a randomized trial

BACKGROUND: A randomized clinical trial was performed to clarify whether continuous use of methimazole (MTZ) during radioiodine ((131)I) therapy influences the final outcome of this therapy. DESIGN: Consecutive patients with Graves' disease (n = 30) or a toxic nodular goiter (n = 45) were rendered euthyroid by MTZ and randomized to stop MTZ 8 d before (131)I (-MTZ; n = 36) or to continue MTZ until 4 wk after (131)I (+MTZ; n = 39). Calculation of the (131)I activity included an assessment of the (131)I half-life and the thyroid volume. RESULTS: The 24-h thyroid (131)I uptake was lower in the +MTZ group than in the -MTZ group (44.8 +/- 15.6% vs. 62.1 +/- 9.9%, respectively; P < 0.001). At 3 wk after therapy, no significant change in serum free T(4) index was observed in the +MTZ group (109 +/- 106 vs. 83 +/- 28 nmol/liter at baseline; P = 0.26), contrasting an increase in the -MTZ group (180 +/- 110 vs. 82 +/- 26 nmol/liter; P < 0.001). The number of cured patients was 17 (44%) and 22 (61%) in the +MTZ and -MTZ groups, respectively (P = 0.17). Cured patients tended to have a lower 24-h thyroid (131)I uptake (50.1 +/- 13.8% vs. 56.4 +/- 17.1%; P = 0.09). By adjusting for a possible interfactorial relationship through a regression analysis (variables: randomization, 24- and 96-h thyroid (131)I uptake, type and duration of disease, age, gender, presence of antithyroid peroxidase antibodies, thyroid volume, dose of MTZ), only the continuous use of MTZ correlated with treatment failure (P = 0.006), whereas a low 24-h thyroid (131)I uptake predicted a better outcome (P = 0.006). CONCLUSION: Continuous use of MTZ hinders an excessive increase of the thyroid hormones during (131)I therapy of hyperthyroid diseases. However, such a strategy seems to reduce the final cure rate, although this adverse effect paradoxically is attenuated by the concomitant reduction of the thyroid (131)I uptake.     

Influence of short-term interruption of antithyroid drugs on the outcome of radioiodine therapy of Graves' disease: results of a prospective study.

AIM: The factors influencing success of treating Graves' disease with radioiodine ( (131)I) are discussed controversially. This study analyses prospectively the influence of discontinuing antithyroid drugs (ATD) immediately prior to treatment with radioiodine on the therapeutic outcome. METHODS: We studied 141 patients with Graves' disease. In 73 of them (group A) treatment was performed under medication with ATD, in 68 patients (group B) ATD were discontinued for 3 - 7 days starting at the time of therapy. We performed a statistical analysis of the influence of ATD and other factors potentially influencing treatment results. RESULTS: In group A 49/73 patients were treated successfully (67 %) vs. 58/68 (85 %) in group B (p < 0.01). Characteristic changes in the kinetics of radioiodine were observed: after discontinuing ATD specific uptake was higher (2.0 %/ml in group A vs. 2.6 %/ml in group B, p = 0.004), and the effective half life was longer (5.1 +/- 1.3 d in group A vs. 5.5 +/- 1.1 d in group B, p = 0.076) resulting in a significantly higher radiation dose in group B (200 +/- 61 Gy in group A vs. 236 +/- 72 Gy in group B, p = 0.002). CONCLUSION: We conclude that short-term interruption of ATD improves the success rate of treating Graves' disease with radioiodine significantly.     

Optimized radioiodine therapy of Graves' disease: analysis of the delivered dose and of other possible factors affecting outcome.

The best approach to radioiodine dose selection in the treatment of Graves' hyperthyroidism remains highly controversial. The formula to calculate the individual dose of (131)I to be delivered has been used for half a century and takes into account the thyroid mass, the effective half-life and the maximum uptake of (131)I. The objective of the present study was to evaluate the accuracy of this formula by determining the relationship between the administered dose of (131)I calculated to deliver a target dose of 50Gy to the thyroid and the actual exact organ dose. We further analyzed if therapeutic success, defined by euthyroidism following the individually calculated dose, can be predicted by different pretreatment parameters and particularly by organ dose. One hundred patients with a first episode of Graves' disease and who had received optimal thyroid irradiation after precise dosimetry were retrospectively reviewed. The patients were categorized according to their thyroid function (plasma free thyroxine (T(4)) serum concentration) as eu-, hyper- or hypothyroid during and 1 year after treatment. The relationship between the administered dose and organ dose was assessed by simple regression. We compared free T(4), free tri-iodothyronine, thyroid weight, the number of patients with antithyroperoxidase antibodies and TSH receptor autoantibodies, 24h urinary iodine excretion, (131)I uptake, and the exact dose of (131)I delivered to the thyroid as pretreatment variables. Although we found a correlation between administered dose (mCi) and organ dose (Gy) (r=0.3, P=0.003), the mean coefficient of variation for organ dose was 45%. Individualized radioiodine therapy enabled euthyroidism in 26% of patients and failed in 74% of patients (33% had persistent or recurrent hyperthyroidism and 41% permanent hypothyroidism). (131)I uptake was significantly higher in the hyperthyroidism group in comparison with the euthyroid group. However, organ dose and other pretreatment variables did not differ among the three groups. In conclusion, these results confirm the low performance of individual dosimetry using what are established ratios, since the delivered dose to the gland, although correlated to the intended dose, is highly variable. The finding that other usual pretreatment variables are not different between groups, gives little hope for improving the way of calculating the ideal dose of radioiodine. We suggest to those not yet ready to give a standard or an ablative dose for Graves' hyperthyroidism that they abandon this way to calculate the (131)I dose.