Comparison of different regimens of glucocorticoid replacement therapy in patients with hypoadrenalism

Since the optimal glucocorticoid replacement needs to avoid over and under treatment, the adequacy of different daily cortisone acetate (CA) doses was assessed in 34 patients with primary and central hypoadrenalism. The conventional twice CA 37.5 mg/day dose was administered to all patients (A regimen: 25 mg at 07:00 h, 12.5 mg at 15:00 h), while in 2 subgroups of 12 patients the dose was shifted on 2 thrice daily regimens (B: 25 mg at 07:00, 6.25 mg at 12: 00, 6.25 mg at 17:00; C: 12.5 mg, 12.5 mg, 12.5 mg). In other 12 patients the conventional dose was reduced to a thrice 25 mg/day administration (D regimen: 12.5 mg, 6.25 mg, 6.25 mg). In all patients, urinary free cortisol (UFC) excretion and cortisol day curves were evaluated. During the CA 37.5 mg administration, nadir cortisol levels were significantly higher with the thrice daily regimens (143 +/- 31 on B and 151 +/- 34 nmol/l on C) than with the conventional twice (85 +/- 16 nmol/l). Moreover, UFC, morning cortisol levels and mean cortisol day curves were similar in each group. Finally, during D regimen nadir cortisol levels were higher than in A and similar to B and C regimens. No difference in UFC and in cortisol day curves by reducing the CA dose was found. In conclusion, the thrice daily cortisone regimens, in which more physiological cortisol levels are achieved, perform better as replacement therapy. The administration of 25 mg/day CA confirms that replacement therapy is more adequate with a lower dose, particularly in patients with central hypoadrenalism.     

Urinary free cortisol increases in adolescent caucasian females during perimenarche

Urinary free cortisol (UFC) excretion has been thought to be constant during female reproductive maturation when normalized for body surface area. We sought to determine whether there are longitudinal changes in urinary free cortisol excretion during perimenarche in adolescent females. We performed a longitudinal study of 24-h UFC excretion obtained at 6-month intervals over a 4-yr period in a cohort of 112 adolescent non-Hispanic white perimenarchal females from south central Pennsylvania. The overall mean values (mean +/- SD) for UFC/24 h for all measurements between ages 12 and 17 yr was 67.4 +/- 43.8 micro g/24 h (to convert to nanomoles per day, multiply by 2.759). In our model, we found a significant positive association between UFC excretion with both gynecological age (P = 0.002) and chronological age (P = 0.0001). For every incremental increase in Tanner stage, the UFC/BSA increased by 3.0 microg/24 h per square meter. Correcting the UFC values by both creatinine and BSA creates a fairly constant number (6.3 +/- 3.1 microg/mg per square meter per 24 h) over the age range 12-17 yr represented in this study. An increase in cortisol excretion may be part of normal reproductive maturation.     

1,25-Dihydroxyvitamin D3 modulates glucocorticoid-induced alteration in serum bone Gla protein and bone histomorphometry

Glucocorticoid excess is associated with alterations in the vitamin D endocrine system. The aim of this study was to assess change in serum bone Gla protein (BGP) after low and high dose cortisone acetate treatment and to assess whether these alterations are altered or attenuated by 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] administration. Five groups of rats were studied and compared to a control group [cortisone acetate in doses of 0.2, 3.3, and 5.0 mg/100 g BW; 1,25-(OH)2D3 in a dose of 100 ng/100 g BW; and a combination of 1,25-(OH)2D3 (100 ng/100 g BW) plus cortisone acetate (3.3 mg/100 g BW)]. Each animal received daily sc injections for 27 days. BGP decreased significantly by day 7 in the two groups receiving high doses of cortisone acetate compared to control group values (65.20 +/- 4.38 vs. 150.18 +/- 6.13 ng/ml in the intermediate dose group and 91.57 +/- 5.30 vs. 150.18 +/- 6.13 ng/ml in the high dose group; P less than 0.01); this effect persisted until day 28. Histomorphometry revealed decreased formation and resorption in the two high dose cortisone acetate groups, whereas low dose cortisone acetate produced no histological change. The combination therapy lessens any change in BGP until day 28 when BGP was lower than the control value (P less than 0.01); histomorphometry showed that combination therapy prevents the effect of cortisone acetate by increasing bone formation and resorption. The data demonstrate that high doses of cortisone acetate suppress bone formation and that this is reflected in the low serum BGP values. Thus, BGP may be a marker of glucocorticoid-induced bone disease. 1,25-(OH)2D3 protects against glucocorticoid-induced bone disease and the normal BGP level reflects this.     

Dose distribution in hydrocortisone replacement therapy has a significant influence on urine free cortisol excretion.

We investigated the influence of dose distribution in hydrocortisone replacement therapy on urine free cortisol excretion. To this end, we measured 24-hour urine free cortisol (24-h UFC) in 13 patients with hypocortisolism. The patients took 25 mg hydrocortisone/day according to the following schedules: either a single 25 mg hydrocortisone dose at 8:00 a.m., or 15 mg hydrocortisone at 8:00 a.m. and 10 mg hydrocortisone at 2:00 p.m., or 5 mg hydrocortisone at 8:00 a.m., 10:00 a.m., 2:00 p.m., 6:00 p.m. and 10:00 p.m. 24-h UFC decreased significantly with increasing division of the daily 25 mg hydrocortisone dose. When taking 25 mg hydrocortisone in a single morning dose, the mean 24-h UFC was 649 +/- 52 nmol/day (mean +/- SEM). When the daily dose was divided into doses of 15 mg and 10 mg hydrocortisone, 24-h UFC was reduced by 28 % to 466 +/- 39 nmol/day (p < 0.002). After division into five doses of 5 mg, 24-h UFC was reduced by 42.8 % to 371 +/- 36 nmol/day (p < 0.001) compared to the single 25 mg dose. These data demonstrate that consideration of the dose distribution in hydrocortisone replacement therapy when analysing 24-h UFC is of clinical importance.     

Hypothalamic-pituitary-adrenal activity in type 2 diabetes mellitus: role of autonomic imbalance

Symptomatic diabetic neuropathy has been found to be associated with hypothalamus-pituitary-adrenal (HPA) axis hyperfunction, but no data are available about HPA activity in diabetic patients with asymptomatic autonomic imbalance. To evaluate HPA axis activity in patients with type 2 diabetes mellitus (T2DM) in relation to the presence or the absence of subclinical parasympathetic or sympathetic neuronal dysfunction, we performed an observational study on 59 consecutive type 2 diabetic patients without chronic complications and/or symptoms of neuropathy or hypercortisolism. The following were measured: serum cortisol at 08:00 am and at midnight (F8 and F24, respectively), post-dexamethasone suppression cortisol, 24-hour urinary free cortisol (UFC), and morning corticotropin (ACTH). Deep-breathing (DB) and LS (LS) autonomic tests were performed to assess the parasympathetic function; postural hypotension test was performed to evaluate sympathetic activity. Patients were subdivided into 4 groups: subjects with parasympathetic failure (group A), sympathetic failure (group B), both para- and sympathetic failure (group C), and without autonomic failure (group D). Hypothalamus-pituitary-adrenal activity was increased in group A compared with group D (UFC, 48.6 +/- 21.4 vs 21.6 +/- 9.8 microg/24 h, P < .0001; ACTH, 27.0 +/- 8.6 vs 15.7 +/- 5.7 pg/dL, P < .01; F8, 20.4 +/- 4.5 vs 13.6 +/- 3.8 microg/dL, P < .05; post-dexamethasone suppression cortisol, 1.2 +/- 0.4 vs 0.8 +/- 0.6 microg/dL, P < .05, respectively) and group B (UFC, 26.3 +/- 11.0 microg/24 h, P < .0001; ACTH, 19.9 +/- 8.0 pg/dL, P < .05). Regression analysis showed that UFC levels were significantly associated with the deep-breathing test (beta = -0.40, P = .004) and tended to be associated with the lying-to-standing test (beta = -0.26, P = .065), whereas body mass index, glycated hemoglobin, and duration of disease were not. Type 2 diabetic patients with asymptomatic parasympathetic derangement have increased activity of HPA axis, related to the degree of the neuronal dysfunction.     

Effects of carvedilol on plasma levels of interleukin-6 and tumor necrosis factor-alpha in nine patients with dilated cardiomyopathy

OBJECTIVES: Whether beta-blocker therapy changes the circulating levels of cytokines as congestive heart failure improves remains uncertain. METHODS: Nine patients with idiopathic dilated cardiomyopathy, who had previously received conventional treatment and were classified as New York Heart Association (NYHA) functional class II, received carvedilol by stepwise dose increase up to 20 mg daily, and the plasma interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) levels were measured. RESULTS: IL-6 was significantly reduced from 0.80 +/- 0.49 pg/ml before therapy to 0.21 +/- 0.08 pg/ml after carvedilol was increased to 20 mg daily (p < 0.05). Moreover, IL-6 level had already decreased significantly compared to the baseline when the dose of carvedilol had reached 10 mg daily (0.28 +/- 0.12 pg/ml, p < 0.05). TNF-alpha levels did not change significantly. CONCLUSIONS: These results demonstrate that IL-6 concentration is significantly decreased by beta-blocker therapy. The efficacy for heart failure may be related to the change of IL-6 concentration.     

肾上腺占位合并垂体病变的库欣综合征九例临床分析并文献复习

目的探讨垂体及。肾上腺均有病变的库欣综合征患者的病因诊断方法。方法回顾性分析9例垂体及肾上腺均病变的患者,行大小剂量地塞米松抑制试验,查血促。肾上腺皮质激素（ACTH）水平,并行鞍区MRI及肾上腺CT。结果（1）血ACTH值在4例库欣病患者中3例高于正常上限,1例正常。5例非ACTH依赖性库欣综合征患者ACTH均〈20ng／L。（2）大剂量地塞米松抑制试验服药第2日24小时尿游离皮质醇在ACTH依赖组均可被抑制到对照值的20％以下,ACTH非依赖组5例患者均未被抑制到对照的50％以下。（3）术后病理支持临床诊断。结论对于兼有肾上腺及垂体两处病变的库欣综合征患者需采用多种方法进行鉴别,最后的判定是术后病理及疗效。     

Circulating chemoattractants RANTES, negatively related to endogenous androgens, and MCP-1 are differentially suppressed by hormone therapy and raloxifene

BACKGROUND: The cardinal role of chronic inflammation in the development of atherosclerosis is increasingly being recognized. Estrogens may prevent the evolution of atherosclerosis by suppressing immune response. Furthermore, the conflicting reports on the cardiovascular effects of hormone therapy between observational and clinical trials have triggered interest on the effect of alternative therapies on the cardiovascular system. OBJECTIVE: The aim of this study was to assess the effect of estrogen, estrogen-progestin, tibolone and raloxifene therapy on circulating markers of chemotaxis in healthy postmenopausal women. METHODS: Eighty-eight postmenopausal women aged 44-62 years were randomly allocated to daily: (1) conjugated equine estrogens 0.625 mg (CEE), (2) 17beta-estradiol 1mg plus norethisterone acetate 0.5mg (E(2)/NETA), (3) tibolone 2.5mg, (4) raloxifene HCl 60 mg or (5) no treatment. Serum monocyte chemoattractant protein-1 (MCP-1) and regulated upon activation, normal T-cell expressed and secreted (RANTES) were measured at baseline and at 3 months. RESULTS: Endogenous testosterone and free androgen index (FAI) correlated negatively, while SHBG correlated positively with serum RANTES (testosterone: r=-0.27, p=0.033; FAI: r=-0.43, p=0.004: SHBG: r=0.34, p=0.026). Serum MCP-1 decreased significantly in the CEE group (baseline 125.3+/-51 pg/ml, 3 months 84.5+/-36.1 pg/ml, p=0.043), while no difference was detected between baseline and post-treatment levels in the other groups. Furthermore, a significant decrease in serum RANTES was observed at the end of 3 months only in the E2/NETA and the raloxifene group (E2/NETA baseline 8690.6+/-3880.0 pg/ml, 3 months 6894.0+/-1720.0 pg/ml, p=0.007; raloxifene baseline 9042.4+/-3765.6 pg/ml, 3 months 6718.1+/-2366.2 pg/ml, p=0.011). CONCLUSION: Endogenous androgens may suppress chemotactic response. Postmenopausal hormone therapy and raloxifene may inhibit the expression of chemoattractant molecules and thus attenuate inflammation. The relevance of these findings in terms of clinically established caridoprotection remains to be clarified.     

Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low-T3 syndrome: a randomized, placebo-controlled study

CONTEXT: Low-T(3) syndrome is a predictor of poor outcome in patients with cardiac dysfunction. The study aimed to assess the short-term effects of synthetic L-T(3) replacement therapy in patients with low-T(3) syndrome and ischemic or nonischemic dilated cardiomyopathy (DC). DESIGN: A total of 20 clinically stable patients with ischemic (n = 12) or nonischemic (n = 8) DC were enrolled. There were 10 patients (average age 72 yr, range 66-77; median, 25-75th percentile) who underwent 3-d synthetic L-T(3) infusion (study group); the other 10 patients (average age 68 yr, range 64-71) underwent placebo infusion (control group). Clinical examination, electrocardiography, cardiac magnetic resonance, and bio-humoral profile (free thyroid hormones, TSH, plasma renin activity, aldosterone, noradrenaline, N-terminal-pro-B-Type natriuretic peptide, and IL-6) were assessed at baseline and after 3-d synthetic L-T(3) (initial dose: 20 microg/m(2) body surface.d) or placebo infusion. RESULTS: After T(3) administration, free T(3) concentrations increased until reaching a plateau at 24-48 h (3.43, 3.20-3.84 vs. 1.74, 1.62-1.93 pg/ml; P = 0.03) without side effects. Heart rate decreased significantly after T(3) infusion (63, 60-66 vs. 69, 60-76 beats per minute; P = 0.008). Plasma noradrenaline (347; 270-740 vs. 717, 413-808 pg/ml; P = 0.009), N-terminal pro-B-Type natriuretic peptide (3000, 438-4005 vs. 3940, 528-5628 pg/ml; P = 0.02), and aldosterone (175, 152-229 vs. 231, 154-324 pg/ml; P = 0.047) significantly decreased after T(3) administration. Neurohormonal profile did not change after placebo infusion in the control group. After synthetic L-T(3) administration, left-ventricular end-diastolic volume (142, 132-161 vs. 133, 114-158 ml/m(2) body surface; P = 0.02) and stroke volume (40, 34-44 vs. 35, 28-39 ml/m(2) body surface; P = 0.01) increased, whereas external and intracardiac workload did not change. CONCLUSIONS: In DC patients, short-term synthetic L-T(3) replacement therapy significantly improved neuroendocrine profile and ventricular performance. These data encourage further controlled trials with more patients and longer periods of synthetic L-T(3) administration.     

Simvastatin inhibits interleukin-6 release in human monocytes stimulated by C-reactive protein and lipopolysaccharide

BACKGROUND: The accumulating evidence suggests that C-reactive protein (CRP) may have direct inflammatory effects on the vascular wall and that statin therapy may have important non-lipid anti-inflammatory effects confirmed by decreasing serum inflammatory markers, such as CRP. However, the effect of simvastatin on interleukin-6 (IL-6) release in cultured human monocytes was not investigated.DESIGN A prospective, human monocyte culture, simvastatin intervention study. METHODS: Monocytes were isolated from blood of healthy volunteers by the Ficoll density gradient and stimulated by broad concentrations of CRP (1-20 microg/ml) and lipopolysaccharide (LPS, 1-10 ng/ml) at indicated time points (0, 2, 4, 8, 16 and 24 h). Also 10-8-10-6 mol/l simvastatin was coincubated with cells in the presence of CRP and LPS. Measurements of IL-6 were performed from supernatants of cultured medium in duplicate, using a commercial assay kit. RESULTS: CRP and LPS induced the rapid release of IL-6, with significantly elevated levels in cultured supernatants at 4 h in the CRP group and at 2 h in the LPS group. The effects of CRP and LPS on IL-6 release of monocytes were dose and time dependent. A greater than 11-fold increase of IL-6 in the CRP group (20 microg/ml) and a greater than 26-fold increase in the LPS group (10 ng/ml) were observed at 24 h compared with the control group (945.7+/-98.3 pg/ml compared with 94.3+/-12.4 pg/ml and 1720.4+/-690.1 pg/ml compared with 70.1+/-16.7 pg/ml, P<0.001, respectively). However, 10-8-10-6 mol/l simvastatin inhibited significantly the production of IL-6 in monocytes stimulated by CRP and LPS in a dose-dependent manner, with the maximal inhibiting effect at a concentration of 10-6 mol/l (945.7+/-98.3 pg/ml compared with 180.9+/-31.2 pg/ml and 1720.4+/-690.1 pg/ml compared with 824.0+/-206.2 pg/ml, P<0.001 respectively). CONCLUSIONS: CRP and LPS could induce IL-6 release in human monocytes and simvastatin could inhibit this response in a dose-dependent manner, which may provide an insight into the mechanisms of anti-inflammatory or anti-atherosclerotic actions of simvastatin.     

内毒素血症时肝窦内皮细胞脂多糖受体CD14蛋白表达的观察

目的观察内毒素血症时肝窦内皮细胞(LSECs)中CD14蛋白合成和CD14 基因的表达,以及CD14蛋白在内毒素介导LSECs激活中的作用. 方法经尾静脉注入脂多糖(LPS,E coli O111B4)5mg/kg,建立大鼠内毒素血症动物模型,分别于术后0(对照组)、3、6、12、24h活杀取材.用兔抗鼠CD14抗体和异硫氢酸荧光素(FITC)标记的羊抗兔IgG对LSECs进行孵育后,流式细胞仪测定LSECs的平均荧光强度(MFI)及FITC阳性细胞数;用原位杂交法测定LSEC中CD14 mRNA的表达.用原位胶原酶灌注法分离大鼠LSECs,用不同浓度LPS(0、0.01、1、10、100μg/ml)刺激LSECs.并用CD14抗体阻断LSECs的 CD14蛋白后,再用不同浓度LPS(0、0.01、1、10、100μg/ml)刺激LSECs.测定LPS介导LSECs肿瘤坏死因子(TNF)-α及白细胞介素-6(IL-6)分泌及CD14抗体对LSECs细胞因子分泌的影响. 结果内毒素血症大鼠3、6、12和24h 时LSECs的MFI明显增加;FITC阳性细胞数也明显增多,分别为54.32%、65.83%、85.61%和45.65%,与对照组的4.45%比较差异有非常显著意义(P＜0.01).原位杂交显示,内毒素血症大鼠LSECs中CD14 mRNA的表达明显增强,而对照组CD14 mRMA无阳性表达.LPS组TNF-α的含量(pg/ml)分别为54.49±6.02、84.65±10.16、206.54±23.55、349.87±39.47和365.76±40.31;CD14阻断组TNF-α的含量(pg/ml)分别为55.93±6.95、63.32±7.81、85.34±9.72、112.75±13.54、198.66±21.54;两组间比较差异有非常显著意义(P＜0.01).LPS组IL-6的含量(pg/ml)分别为103.34±12.52、187.39±20.31、243.87±27.83、289.51±30.15、298.53±31.94;CD14阻断组IL-6的含量(pg/ml)分别为104.37±11.49、125.02±13.58、164.59±19.47、183.47±20.17、221.76±26.43;两组间比较差异有非常显著意义(P＜0.01). 结论内毒素血症时LSECs能合成CD14蛋白及表达CD14基因;抗CD14抗体对LPS诱导LSECs TNF-α和IL-6的分泌有抑制作用;CD14蛋白的表达在内毒素介导LSECs激活中可能起重要作用.     

Effects of rosuvastatin on progression of stenosis in adult patients with congenital aortic stenosis (PROCAS Trial)

Recent trials have failed to show that statin therapy halts the progression of calcific aortic stenosis (AS). We hypothesized that statin therapy in younger patients with congenital AS would be more beneficial, because the valve is less calcified. In the present double-blind, placebo-controlled trial, 63 patients with congenital AS (age 18 to 45 years) were randomly assigned to receive either 10 mg of rosuvastatin daily (n = 30) or matched placebo (n = 33). The primary end point was the progression of peak aortic valve velocity. The secondary end points were temporal changes in the left ventricular mass, ascending aortic diameter, and N-terminal pro-brain natriuretic peptide (NT-proBNP). The median follow-up was 2.4 years (interquartile range 1.9 to 3.0). The mean increase in peak velocity was 0.05 ± 0.21 m/s annually in the rosuvastatin group and 0.09 ± 0.24 m/s annually in the placebo group (p = 0.435). The annualized change in the ascending aorta diameter (0.4 ± 1.7 mm with rosuvastatin vs 0.5 ± 1.6 mm with placebo; p = 0.826) and left ventricular mass (1.1 ± 15.8 g with rosuvastatin vs -3.7 ± 30.9 g with placebo; p = 0.476) were not significantly different between the 2 groups. Within the statin group, the NT-proBNP level was 50 pg/ml (range 19 to 98) at baseline and 21 pg/ml (interquartile range 12 to 65) at follow-up (p = 0.638). NT-proBNP increased from 40 pg/ml (interquartile range 20 to 92) to 56 pg/ml (range 26 to 130) within the placebo group (p = 0.008). In conclusion, lipid-lowering therapy with rosuvastatin 10 mg did not reduce the progression of congenital AS in asymptomatic young adult patients. Interestingly, statins halted the increase in NT-proBNP, suggesting a potential positive effect of statins on cardiac function in young patients with congenital AS.     

Treatment of shigellosis: III. Comparison of one- or two-dose ciprofloxacin with standard 5-day therapy. A randomized, blinded trial.

OBJECTIVE: To determine whether a single dose, or 2 doses, of ciprofloxacin are as effective as 5-day, 10-dose therapy for the treatment of shigellosis in adult men who are moderately to severely ill. DESIGN: Randomized, double-blind clinical trial. SETTING: A diarrhea treatment center in the capital city of a developing country, Bangladesh. PATIENTS: A total of 128 adult men with dysentery of less than 96 hours duration. All had Shigella organisms isolated from a culture of stool. INTERVENTIONS: Patients were randomly assigned to receive either a single 1-gram dose of ciprofloxacin at admission to the study (single-dose group; n = 40), a 1-gram dose of ciprofloxacin at admission and 24 hours later (2-dose group; n = 43), or 500 mg of ciprofloxacin every 12 hours for 5 days (10 dose group; n = 35). All patients were hospitalized for 6 days. MEASUREMENTS: Stools were collected individually; their character and consistency were recorded and cultured daily. A physical examination and recording of symptoms were done daily, and the temperature was measured every 4 hours. Therapy was considered to have failed in patients who did not have improvement in the signs and symptoms of dysentery after 72 hours of therapy or in patients who on study day 5 had more than nine stools, or more than two watery stools, or were febrile. RESULTS: There were no treatment failures in the 78 patients infected with species of Shigella other than Shigella dysenteriae type 1. Among the 40 patients infected with S. dysenteriae type 1, treatment failed in 4 of the 10 patients who received single-dose therapy, 2 of the 15 patients who received 2-dose therapy, and none of the 15 patients who received 10-dose therapy (P = 0.017, single-dose therapy group compared with 10-dose group; P = 0.15 for the single-dose group compared with the 2-dose group; P > 0.2 for the 2-dose group compared with the 10-dose group). CONCLUSIONS: A single 1-gram dose of ciprofloxacin is effective therapy for patients infected with species of Shigella other than S. dysenteriae type 1. Single-dose therapy is inferior to 10-dose therapy for treating patients infected with S. dysenteriae type 1.     

Serum level of vascular endothelial growth factor is decreased by hormone replacement therapy in postmenopausal women without hypercholesterolemia

The administration of hormone replacement therapy (HRT) to postmenopausal women (PMW) reportedly has beneficial effects on their levels of lipid and lipoproteins. Estrogen retards the development of atherosclerosis induced by a high-fat diet in animals. Although vascular endothelial growth factor (VEGF) may be involved in the development of atherosclerosis in humans, there is no information on effect of estrogen administration on VEGF level and lipid metabolism. We evaluated 64 healthy normotensive or hypertensive PMW before and during the administration of HRT (0.625 mg conjugated equine estrogen combined with 2.5 mg medroxyprogesterone acetate orally) daily for 6 months. All hypertensive PMW were well-controlled on antihypertensive drug therapy. According to their total cholesterol level at baseline, we divided the PMW with HRT (n=54) into a normocholesterolemic group (NC, total cholesterol <220 mg/dl, n=35) and a hypercholesterolemic group (HC, total cholesterol >/=220 mg/dl, n=19). We evaluated the serum levels of VEGF at baseline, and again at 3 and 6 months after starting HRT. HRT significantly (P<0.01) reduced the mean VEGF level from 31.5+/-4.3 pg/ml at baseline to 18.2+/-2.3 pg/ml after 6 months in the NC group. However, the VEGF levels in the HC group and the control group exhibited no significant change at either 3 or 6 months after starting HRT. In summary, HRT, using a combination of conjugated equine estrogen and medroxyprogesterone acetate, reduced the level of VEGF in normocholesterolemic PMW more effectively than in those with hypercholesterolemia.     

Effect of omeprazole on serum gastrin levels: influence of age and sex

Serum gastrin levels were determined in 120 consecutive patients (43 females, 77 males) with peptic disease 24 h post dose after 4 weeks continuous omeprazole (40 mg daily) treatment. Serum gastrin levels were elevated in 33 (28%) but exceeded the twice normal range in only 6 patients (5%). Age and sex did not influence the magnitude of gastrin levels. Gastrin increments induced by omeprazole compared to pretreatment with H2-blockers in 60 cases were similar in both males (42 +/- 10 pg/ml) and females (44 +/- 9 pg/ml). It is concluded that the magnitude of gastrin increases observed during omeprazole therapy are small and independent of age and sex.     

The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism

Calcimimetics increase the sensitivity of the calcium-sensing receptor (CaR) to circulating serum calcium, reducing the secretion of PTH and the serum calcium concentration. We evaluated the calcimimetic cinacalcet, a novel therapy for the management of primary hyperparathyroidism. In this randomized, double-blind, dose-finding study, patients (n = 22) with primary hyperparathyroidism were given cinacalcet (30, 40, or 50 mg) or placebo twice daily for 15 d and observed for an additional 7 d. Serum calcium, plasma PTH, and 24-h and fasting urine calcium were measured. Baseline mean serum calcium was 10.6 mg/dl for the combined cinacalcet-treated patients (normal range, 8.4-10.3 mg/dl), compared with 10.4 mg/dl for the placebo group. Mean PTH at baseline was 102 pg/ml (normal range, 10-65 pg/ml) for the combined cinacalcet-treated patients, compared with 100 pg/ml in the placebo group. Serum calcium normalized after the second dose on d 1 and remained normal through d 15 in all cinacalcet dose groups. Maximum decreases in PTH of over 50% occurred 2-4 h after dosing in all cinacalcet-treated groups. The fasting and 24-h urine calcium to creatinine ratios were similar in the cinacalcet and placebo groups. This study demonstrates that cinacalcet safely normalized serum calcium and lowered PTH concentrations without increasing urinary calcium excretion in the study subjects, indicating the potential benefit of cinacalcet as a medical treatment for primary hyperparathyroidism.     

Prostacyclin: its pathogenic role in essential hypertension and the class effect of ACE inhibitors on prostaglandin metabolism

Angiotensin-converting enzyme inhibitors (ACEI) block degradation of bradykinin, and bradykinin stimulates prostacyclin synthesis. Therefore, we set out to determine whether the effects of ACE inhibitors on prostaglandin production in essential hypertensive patients are class effects or are dependent on ACE inhibitor structure. In addition, we studied whether hypertensives show an impaired capacity to synthesize vasodilator prostaglandins. To address these questions, we compared the effects of captopril (sulfhydryl-containing inhibitor), enalapril and ramipril (carboxyl-containing inhibitors) and fosinopril (phosphoryl-containing inhibitor) on blood pressure and urinary excretion of 6-keto-prostaglandin (PG) F1-alpha (the breakdown product of prostacyclin) in 44 mild-to-moderate essential hypertensive subjects before and 8 weeks after administration of an ACEI. We also studied prostacyclin excretion in 15 normotensive healthy controls. Levels of urinary 6-keto-PGF1-alpha (pg/ml) were measured by specific radioimmunoassay. Hypertensive subjects showed a lower excretion of 6-keto-PGF1-alpha than normotensive controls (212+/-147 vs 353+/-98 pg/ml, p < 0.001). All ACEI induced a significant decrease in MAP and increased the rate of excretion of the prostacyclin metabolite: C, 211+/-200 to 338+/-250 pg/ml, p < 0.05; E, 202+/-133 to 296+/-207 pg/ml, p < 0.05; R, 205+/-127 to 342+/-211 pg/ml, p < 0.05; F, 235+/-128 to 347+/-241 pg/ml, p < 0.05. In hypertensives (n = 44) the decrease in blood pressure correlated negatively with the rise in 6-keto-PGF1-alpha excretion (r = -0.51, p < 0.001). These data suggest that impaired prostacyclin biosynthesis in hypertensive patients could account for haemodynamic changes leading to the hypertensive state. Moreover, the hypotensive mechanisms of ACEI may be mediated by an increase in prostacyclin production; this effect seems to be class-dependent.     

Lowering the dose of hydroxyurea minimizes toxicity and maximizes anti-HIV potency

The goal of this study was to optimize the hydroxyurea dosage in HIV-infected patients, and to minimize the toxicity and maximize the antiviral efficacy of the hydroxyurea-didanosine combination. In a randomized, open-label study (RIGHT 702, a multicenter trial performed in private and institutional practices), three daily doses (600 microg, 800-900 microg, and 1200 microg) of hydroxyurea were administered in combination with didanosine and stavudine to 115 chronically HIV-infected patients, one-third antiretroviral drug naive, with viremia between 5000 and 200,000 copies/ml regardless of CD4+ cell count. The primary efficacy end point was the proportion of patients with plasma HIV-1 RNA levels below 400 copies/ml after 24 weeks of therapy. In the RIGHT 702 intent-to-treat population the lowest (600 mg) dose of hydroxyurea was better tolerated, associated with fewer adverse events, and more potent by all efficacy parameters, including the primary end point (76 versus 60% patients with viremia<400 copies/ml at week 24 for the 600-mg and 800- to 900-mg dose groups, respectively; p=0.027), the mean area under the curve (60.3 versus 65.8; p=0.016), and the mean log10 decrease (-1.95 versus -0.77; p=0.001). Patients receiving 600 mg of hydroxyurea daily also had the highest CD4+ cell count, CD4+/CD8+ cell ratio, and lowest CD8+ cell count and percentage (p=0.035). The RIGHT 702 trial provides an explanation for the increased toxicity and decreased efficacy of hydroxyurea when it was used at high dosage (1200 mg daily). At the optimal dosage of 600 mg daily, hydroxyurea, in combination with didanosine, deserves reevaluation for the long-term management of HIV/AIDS worldwide, because of its excellent resistance profile, durability, and affordability.     

Cladribine decreases the level of angiogenic factors in patients with chronic lymphocytic leukemia

We investigated the serum concentration of basic fibroblast growth factor (bFGF) and transforming growth factor beta1 (TGFbeta1), using an enzyme linked immunosorbent assay (ELISA) in a group of 18 chronic lymphocytic leukemia (CLL) patients, before and after a successful treatment with cladribine (2-chlorodeoxyadenosine, 2-CdA) and 16 healthy volunteers. The serum level of bFGF was found to be significantly lower in the control group (median 0.15 pg/ml, range 0.0-15.7 pg/ml), when compared to the untreated CLL patients (median 41.4 pg/ml, range 2.1-292.6 pg/ml) (p=0.0002). After a successful 2-CdA treatment we observed a significantly lower level of this cytokine (median 10.55 pg/ml, range 0.4-140.4 pg/ml) (p=0.0019) in the same patients. However, the level of bFGF in this group was still higher than in the control group (p=0.003). The levels of TGFbeta1 were higher in the group of untreated CLL patients (median 31.36 ng/ml, range 14.36-75.71 ng/ml) than in the control group (median 28.35 ng/ml, range 10.85-70.10 ng/ml) (p=0.029). After the 2-CdA treatment serum concentration of this cytokine decreased significantly (median 20.34 ng/ml, range 3.02-43.85 ng/ml) (p=0.031) with similar levels present to that of the healthy control group (p=0.3). In conclusion, we have shown that the serum concentration of bFGF and TGFbeta1 in CLL patients were significantly reduced after 2-CdA chemotherapy that resulted in remission. The level of these factors might correlate with the activity of the disease.     

Plasma human atrial natriuretic peptide, endothelin-1, aldosterone and plasma-renin activity in pregnancy-induced hypertension.

OBJECTIVE: To determine the relationship between endothelin-1 (ET-1), human atrial natriuretic peptide (hANP), plasma-renin activity (PRA) and 24-h urinary excretion of aldosterone (U-Ald) in pregnancy-induced hypertension (PIH). DESIGN AND METHODS: Plasma hANP (pg/ml), ET-1 (pg/ml), PRA (ng/ml per h) and U-Ald (microg/24 h) were measured and 24 h ambulatory mean arterial pressure (MAP) was monitored in 178 normotensive subjects (NT) and 79 gravidas with PIH at the 8th, 18th, 23rd, 28th, 32nd and 36th weeks. RESULTS: The PIH group had higher MAP than the NT group from the 23rd week (91.64 +/- 8.76 versus 83.48 +/- 4.36 mmHg, P< 0.01) until the end of the pregnancy. ET-1 levels (pg/ml) in both groups were identical at the beginning of pregnancy and different in the 23rd week [(NT versus PIH) (35.11 +/- 17.42 and 40.2 +/- 19.51, respectively, P < 0.05)] and the 36th week (37.36 +/- 18.07 and 42.7 +/- 16.43, P< 0.05). hANP levels (pg/ml) in the NT group decreased insignificantly from the 8th till the 32nd week, then increased to 101.94 +/- 17.4 in the 36th (P< 0.001 versus any other week). In the PIH group, hANP increased from 104.8 +/- 26.8 pg/ml at the 8th week to 161.3 +/- 28.6 pg/ml at the 36th week (P< 0.0001). hANP correlated with MAP in the NT group (r = 0.252, P< 0.0005) but not the PIH group. U-Ald in the NT group increased from 23.52 +/- 6.83 microg/24 h at the 8th week to 54.07 +/- 19.62 microg/24 h at the 36th week (P < 0.0001) and in the PIH group it increased from 27.90 +/- 11.6 to 53.66 +/- 20.4 microg/24 h (P< 0.0001). In the PIH group, PRA was lower compared with the NT group from the 8th (2.99 +/- 1.26 versus 4.10 +/- 1.82 ng/ml per h, P< 0.05) until the 36th week (3.34 +/- 2.16 versus 4.46 +/- 2.13 ng/ml per h). In the forced multiple regression analysis model with hANP as a dependent variable, a value of P< 0.003 was found with PRA, U-Ald and MAP, which indicates an interaction between the two vasoactive and homeostatic systems: the renin-angiotensin-aldosterone system and hANP. CONCLUSIONS: In PIH, elevated hANP might be important as a counterbalance to the presence of the active vasopressors and sodium retention. By inhibiting renin release, enhancing the transcapillary fluid migration and with its action as vasodilator, it acts as a corrective factor of the imbalance between the contracted circulating fluid volume and the vasoconstricted vascular bed.