Pituitary responsiveness to GH-releasing hormone, GH-releasing peptide-2 and thyrotrophin-releasing hormone in critical illness

OBJECTIVE Protein hypercatabolism and preservation of fat depots are hallmarks of critical illness, which is associated with blunted pulsatile GH secretion and low circulating IGF-I, TSH, T4 and T3. Repetitive TRH administration is known to reactivate the pituitary-thyroid axis and to evoke paradoxical GH release in critical illness. We further explored the hypothalamic-pituitary function in critical illness by examining the effects of GH-releasing hormone (GHRH) and/or GH-releasing peptide-2 (GHRP-2) and TRH administration. PATIENTS AND DESIGN Critically ill adults (n=40; mean age 55 years) received two i.v. boluses with a 6-hour interval (0900 and 1500 h) within a cross-over design. Patients were randomized to receive consecutively placebo and GHRP-2 (n=10), GHRH and GHRP-2 (n=10), GHRP-2 and GHRH+GHRP-2 (n=10), GHRH+GHRP-2 and GHRH+GHRP-2+TRH (n=10). The GHRH and GHRP-2 doses were 1μg/kg and the TRH dose was 200μg. Blood samples were obtained before and 20, 40, 60 and 120 minutes after each injection. MEASUREMENTS Serum concentrations of GH, T4, T3, rT3, thyroid hormone binding globulin (TBG), IGF-I, insulin and cortisol were measured by RIA; PRL and TSH concentrations were determined by IRMA. RESULTS Critically ill patients presented a striking GH response to GHRP-2 (mean±SEM peak GH 51±9 μg/l in older patients and 102±2μg/l in younger patients; P=0.005 vs placebo). The mean GH response to GHRP-2 was more than fourfold higher than to GHRH (P=0.007). In turn, the mean GH response to GHRH+GHRP-2 was 2.5-fold higher than to GHRP-2 alone (P=0.01), indicating synergism. Adding TRH to the GHRH+GHRP-2 combination slightly blunted this mean response by 18% (P=0.01). GHRP-2 had no effect on serum TSH concentrations whereas both GHRH and GHRH+GHRP-2 evoked an increase in peak TSH levels of 53 and 32% respectively. The addition of TRH further increased this TSH response < ninefold (P=0.005), elicited a 60% rise in serum T3 (P=0.01) and an 18% increase in T4 (P=0.005) levels, without altering rT3 or TBG levels. GHRH and/or GHRP-2 induced a small increase in serum PRL levels. The addition of TRH magnified the PRL response 2.4-fold (P=0.007). GHRP-2 increased basal serum cortisol levels (531±29nmol/l) by 35% (P=0.02); GHRH provoked no additional response, but adding TRH further increased the cortisol response by 20% (P=0.05). CONCLUSIONS The specific character of hypothalamic-pituitary function in critical illness is herewith extended to the responsiveness to GHRH and/or GHRP-2 and TRH. The observation of striking bursts of GH secretion elicited by GHRP-2 and particularly by GHRH+GHRP-2 in patients with low spontaneous GH peaks opens the possibility of therapeutic perspectives for GH secretagogues in critical care medicine.     

Initial evaluation of123|-5-|-R91150, a selective 5-HT2A ligand for single-photon emission tomography, in healthy human subjects

The mapping of 5-HT₂ receptors in the brain using functional imaging techniques has been limited by a relative lack of selective radioligands. Iodine-123 labelled 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (¹²³I-5-I-R91150 or¹²³I-R93274) is a new ligand for single-photon emission tomography (SPET), with high affinity and selectivity for 5-HT_2A receptors. This study reports on preliminary¹²³I-5-I-R91150 SPET, wholebody and blood distribution findings in five healthy human volunteers. Maximal brain uptake was approximately 2% of total body counts at 180 min post injection (p.i.). Dynamic SPET sequences were acquired with the brain-dedicated, single-slice multi-detector system SEM-810 over 200 min p.i. Early peak uptake (at 5 min p.i.) was seen in the cerebellum, a region free from 5HT_2A receptors. In contrast, radioligand binding in the frontal cortex increased steadily over time, up to a peak at approximately 100–120 min p.i. Frontal cortex-cerebellum activity ratios reached values of 1.4, and remained stable from approximately 100 min p.i. onwards. Multi-slice SPET sequences showed a pattern of regional variation of binding compatible with the autoradiographic data on the distribution of 5-HT_2A receptors in (cerebral cortex>striatum>cerebellum). These findings suggest that¹²³I-5-I-R91150 may be used for the imaging of 5-HT_2A receptors in the living human brain with SPET.     

Role of Tyrosine Kinase in Desflurane-induced Preconditioning

Background: Short administration of volatile anesthetics preconditions myocardium and protects the heart against the consequences of subsequent ischemia. Activation of tyrosine kinase is implicated in ischemic preconditioning. The authors investigated whether desflurane-induced preconditioning depends on activation of tyrosine kinase.

Methods: Sixty-four rabbits were instrumented for measurement of left ventricular pressure, cardiac output, and myocardial infarct size (IS). All rabbits were subjected to 30 min of occlusion of a major coronary artery and 2 h of subsequent reperfusion. Rabbits underwent a treatment period consisting of either no intervention for 35 min (control group, n = 12) or 15 min of 1 minimum alveolar concentration desflurane inhalation followed by a 10-min washout period (desflurane group, n = 12). Four additional groups received the tyrosine kinase inhibitor genistein (5 mg/kg) or lavendustin A (1.3 mg/kg) at the beginning of the treatment period with (desflurane-genistein group, n = 11; desflurane-lavendustin A group, n = 12) or without desflurane inhalation (genistein group, n = 9; lavendustin A group, n = 8).

Results: Hemodynamic values were similar in all groups during baseline (left ventricular pressure, 87 +/- 14 mmHg [mean +/- SD]; cardiac output, 198 +/- 47 ml/min), during coronary artery occlusion (left ventricular pressure, 78 +/- 12 mmHg; cardiac output, 173 +/- 39 ml/min), and after 2 h of reperfusion (left ventricular pressure, 59 +/- 17; cardiac output, 154 +/- 43 ml/min). IS in the control group was 55 +/- 10% of the area at risk. The tyrosine inhibitors had no effect on IS (genistein group, 56 +/- 13%; lavendustin A group, 49 +/- 13%; each P = 1.0 vs. control group). Desflurane preconditioning reduced IS to 40 +/- 15% (P = 0.04 vs. control group). Tyrosine kinase inhibitor administration had no effect on IS reduction (desflurane-genistein group, 44 +/- 13%; desflurane-lavendustin A group, 44 +/- 16%; each P = 1.0 vs. desflurane group).     

An evaluation of the cardiovascular safety profile of duloxetine: findings from 42 placebo-controlled studies.

BACKGROUND AND OBJECTIVE: In recent years, new classes of medication, such as the serotonin-noradrenaline reuptake inhibitors (SNRIs), have been developed for use in the treatment of major depressive disorder (MDD). For many years, treatment options were largely limited to the use of monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). However, there have been published reports of orthostatic hypotension, arrhythmias and corrected QT (QTc) interval changes in patients treated with TCAs. As new medications become available, it is important to understand how their cardiovascular safety profile compares with that of more established agents to aid clinicians and patients in choosing the best treatment options. This study was designed to evaluate the cardiovascular safety profile of the SNRI duloxetine through evaluation of cardiovascular-related parameters and adverse events (AEs). METHODS: The cardiovascular safety of duloxetine was assessed using all placebo-controlled duloxetine clinical trial data as of December 2005. This consisted of data from 42 placebo-controlled clinical trials of 8504 patients who were treated with duloxetine. Additional information from a high-dose clinical pharmacology study and postmarketing safety surveillance are also presented. Of the placebo-controlled trials included in this analysis, clinical indications under investigation included MDD (15 studies), diabetic peripheral neuropathic pain (3 studies), fibromyalgia (2 studies), generalised anxiety disorder (3 studies) and lower urinary tract disorders (19 studies, all related to incontinence). Cardiovascular safety was evaluated based on vital signs, ECGs and the incidence of treatment-emergent AEs potentially related to cardiovascular safety. These safety parameters were analysed across all indications. To identify both serious and non-serious cardiovascular-related AEs, as well as AEs reported as the reason for discontinuation, a comprehensive list of terms derived from the Medical Dictionary for Regulatory Activities (version 8.0) was generated and used to search the duloxetine databases for cardiovascular-related events. RESULTS: Calculation of change from baseline to maximum in ECG parameters showed significant differences between treatment groups for all parameters, with decreases from baseline in RR, QRS and QT intervals for patients receiving duloxetine and increases from baseline for patients treated with placebo. These shifts were related to small heart rate changes, but the mean differences were not considered clinically relevant. Categorical analyses of shifts from normal to abnormal (or abnormal to normal) for heart rate and QT corrected for heart rate using Fridericia's formula (QTcF) values showed that most patients did not shift from their baseline category. Patients with MDD who were treated for up to 1 year with duloxetine had blood pressure changes early in treatment that then stabilised. Even in patients with elevated blood pressure at baseline in these clinical trials, no increased risk of sustained blood pressure elevation with duloxetine treatment was found. CONCLUSION: Overall, the findings presented here support our conclusions that use of duloxetine does not appear to be associated with significant cardiovascular risks in patients with conditions for which the drug has been approved or studied.     

Efficacy and tolerability of a new antipsychotic compound (risperidone): results of a pilot study.

Risperidone is a new benzisoxazole derivative displaying a very potent serotonin antagonism and a potent dopamine antagonism in pharmacological studies. These properties suggest the hypothesis that risperidone may exert antipsychotic effects and be superior to classic neuroleptics in its beneficial effects on negative and affective symptoms and its low extrapyramidal side-effect propensity. In an open pilot study 13 patients suffering from acute schizophrenic psychosis were treated with risperidone within an individually adapted dose range from 1 to 10 mg per day. A good antipsychotic efficacy could be demonstrated in 6 of the 8 patients who completed the trial. Risperidone was very well tolerated. The substance possesses a low EPS-inducing profile. Future research has to test the suggested advantage of risperidone over other neuroleptic drugs and its performance in the treatment of chronic schizophrenic patients.     

实验性单纯疱疹性角膜炎的组织病理学研究

目的：动态观察1型单纯疱疹病毒（HSV－1）感染角膜后的组织病理改变。方法：BALB／c小鼠眼角膜接种HSV－1（KOS株）以诱发单纯疱疹性角膜炎（HSK）。分别收集正常眼球及感染后第2、7、14天的感染眼球，组织学观察结膜及角膜的病理过程。结果：感染后第2天，中性粒细胞、淋巴细胞及其他单核细胞浸润结膜并在第7－14天间快速向中央角膜扩散。结论：在HSK发展中，中性粒细胞浸润导致进行性的组织破坏。     

Dynamic contrast-enhanced MR imaging assessment of vascularized free fibular grafts

Magnetic resonance (MR) imaging may be a noninvasive method for assessing perfusion of vascularized bone grafts placed for treatment of avascular necrosis. One proximal femur of seven beagles was devascularized, with insertion of a vascularized fibular graft. MR imaging at 1 week (seven dogs) and 6 weeks (five dogs) after surgery included pre- and postcontrast spin-echo sequences, unenhanced twodimensional time-of-flight (TOF) vascular imaging, and dynamic gradient-echo imaging during infusion of gadolinium. Relative signal intensity values of selected regions obtained from the dynamic gradientecho images were plotted as percent enhancement versus time. In the operated hip, MR imaging did not show enhancement in six of seven femoral heads and greater trochanters at 1 week after surgery, with similar results after 6 weeks. MR imaging of fibular grafts 6 weeks after surgery showed an initial rapid increase in enhancement and a subsequent slower increase in five of five dogs, although no enhancement was seen in six of seven dogs at 1 week. These findings contrasted with a rapid initial increase in enhancement followed by slow decline in non-operated hips. Two-dimensional TOP imaging did not show the vascular pedicle of the graft in any dog. Findings of radionuclide bone scanning performed 1 week after surgery were consistent with devascularization of the operated femur and fibular graft. However, tetracycline distribution and histologic findings confirmed the viability of five of five grafts within the devascularized femurs 6 weeks after surgery. Thus, dynamic contrast-enhanced MR imaging at 6 weeks after surgery is valuable for assessing vascular bone graft perfusion, while similar imaging at 1 week may suggest otherwise.     

Natural history of parathyroid function and calcium metabolism after kidney transplantation: a single-centre study.

BACKGROUND: The natural history of parathyroid function after successful renal transplantation (RT) and the factors predisposing to persistent hyperparathyroidism (HPT) are not well established. A better knowledge of these data may be helpful in the development of algorithms for optimal surveillance and treatment of HPT after successful RT. Our aim was to evaluate the post-transplant natural history of parathyroid function and calcium metabolism in patients with a functional renal graft and to identify risk factors for persistent HPT. METHODS: Charts of 1165 allograft kidney recipients transplanted between 1989 and 2000 were reviewed. Patients with an intact parathyroid hormone (iPTH) level available at the time of transplantation were identified. The charts of the latter patients were checked for a variety of demographic and clinical data, and all determinations of the iPTH concentration available since transplantation were recorded. Serum levels of calcium, phosphorus, alkaline phosphatases and creatinine, concurrently determined, were also registered. RESULTS: After an initial fall, iPTH levels showed a slow but steady decline towards the upper normal limit. The prevalence of persistent HPT, defined as an iPTH level > or =2.5 times the upper normal limit or the need for parathyroidectomy following transplantation, remained stable at approximately 17% up to 4 years after transplantation. Patients with persistent HPT had significantly elevated serum levels of iPTH, calcium and phosphorus at the time of RT, and had spent a longer time on dialysis. Post-transplant iPTH levels correlated significantly with transplant kidney function. CONCLUSION: Kidney transplant recipients with a high iPTH and calcium x phosphate product at the time of transplantation are at risk for persistent HPT especially when renal function is suboptimal. Therapy for persistent HPT, if considered, should be initiated 3 months post-transplantation since further spontaneous improvement of parathyroid function thereafter is limited.     

Ultrasound-Guided Interstitial Brachytherapy in the Treatment of Advanced Vaginal Recurrences from Cervical and Endometrial Carcinoma

BACKGROUND: In advanced vaginal recurrences of cervical and endometrial carcinomas therapeutic options are rare because of preceding therapy. PATIENTS AND METHODS: 23 patients developing advanced vaginal recurrences of cervical and endometrial carcinomas were included. 15 patients started with external-beam therapy to the pelvis and eight patients after preceding radiotherapy underwent brachytherapy alone. All patients had ultrasound-guided implantation of transvaginal or transperineal interstitial needles for brachytherapy. Median prescribed total dose was 64 Gy. RESULTS: 18 patients (78%) achieved complete remission. Six patients are alive without tumor and one with tumor after a median follow-up of 64 months. 14 patients died of tumor and two of intercurrent disease. 5-year disease-specific survival and local control rate were 43% and 47%, respectively, in patients with complete remission. Univariate analysis found time to relapse > 2 years, initial diameter < or = 4 cm, initial volume < 15 cm(3), no extension to the pelvic side wall, volume before brachytherapy < 7.5 cm(3), brachytherapy coverage index > 0.8, and prescribed total dose > 64 Gy being positive predictors for local control and survival. CONCLUSION: The use of ultrasound guidance for placement of interstitial needles in template-based brachytherapy of advanced recurrent gynecologic malignancies is a feasible, safe, and cheap method with encouraging results. Today, ultrasound imaging can be also used to some extent for treatment planning which requires further development. Patient- and treatment-related prognostic factors can be defined.