Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

Successful treatment of refractory ascites in a child with transjugular intrahepatic portosystemic shunt

A 16-y-old boy who had undergone bone marrow transplantation for relapsed acute lymphoblastic leukaemia developed liver cirrhosis and refractory ascites, which did not respond to salt restriction, diuretics and abdominal paracentesis. Liver transplantation was not feasible because of poor nutritional status, pre-existing renal dysfunction and uncertainty about the prognosis of his leukaemia. The patient underwent a successful transjugular intrahepatic portosystemic shunt (TIPS), with immediate resolution of ascites, enabling cessation of diuretics and improvement in nutritional status. At 24 mo following TIPS there has been no re-accumulation of ascites. CONCLUSION: TIPS may have a role in the management of refractory ascites secondary to liver cirrhosis in selected children.     

埋没导引缝合针在双侧唇裂继发畸形修复中的应用

目的　探讨双侧唇裂继发畸形的解剖学修复。方法　采用埋没导引缝合针缝合法 ,对于引起畸形的主要因素 :鼻翼软骨向两侧移位 ,鼻降肌挛缩 ,口轮匝肌移位 ,鼻孔底瘢痕挛缩等进行彻底松解后 ,牢固准确地复位、固定 ,以恢复其正常的解剖关系。结果　自 1998年以来 ,共收治 2 6例双侧唇裂继发畸形患者 ,除 1例叉状皮瓣远端坏死外 ,余均顺利成功。随访 1～ 2年效果满意。结论　本手术不仅简单省时 ,而且能达到从解剖学角度修复畸形     

Gastrointestinal teratomas: CT and US appearance with pathologic correlation

Gastrointestinal teratomas are uncommon, benign neoplasms that occur primarily in children. A retrospective review of five cases (two gastric, one pancreatic, one mesenteric, and one in the lesser omentum) is presented with emphasis on the computed tomographic and ultrasonographic appearances. Principal findings are a well-defined mass with separate cystic and solid components of varying proportions, discrete areas with densities similar to that of fat, or coarse, globular calcifications within the solid component. Recognition of these findings may allow the radiologist to make a correct preoperative diagnosis of teratoma.     

Expert system-controlled image display

Conventional computer-based medical expert systems deliver advice to physicians as written text. While such advice is useful, it has distinct limitations in a visually oriented discipline such as diagnostic radiology, in which decisions often depend on pattern recognition and appreciation of subtle morphologic features. The authors developed a prototype expert computer system, IMAGE/ICON, which displays groups of images sorted into a series of axes based on different ways in which they may be similar. They may share a common feature, group of features, causes, or clinical setting. IMAGE/ICON may display examples of morphologic variations of a dominant finding or a spectrum of abnormalities seen in an specific disease or group of diseases. The system also assembles a written analysis of key features of a case. Such a tool may be useful as a diagnostic aid or for continuing medical education. It is likely to have particular impact in the form of an intelligent radiologic workstation, as picture archiving and communication systems become available.     

Defects in lens fiber differentiation are linked to c-mos overexpression in transgenic mice

We describe three strains of transgenic mice derived by embryo microinjection of DNA consisting of a long terminal repeat (LTR) of Moloney murine sarcoma virus (Mo-MSV) linked to the murine c-mos coding sequences. Southern analysis of the genomic DNA of these strains suggested that in each case the transgene had integrated at a different chromosomal location. The strains were characterized by dominant changes in secondary lens fiber differentiation. Shortly after birth, insufficient elongation of differentiating lens fibers and lack of basement membrane secretion resulted in breakdown of the posterior lens capsule. This, in turn led to posterior protrusion and swelling of lens tissue. In the course of the first 3 weeks after birth, globular lens cells began to fill the entire anterior and posterior chambers of the eye. Concomitantly, there was massive overexpression of c-mos RNA in the lens. Whereas this construct has high transforming activity when transfected into NIH-3T3 cells, no hyperplasia or neoplasia have been observed in the affected lenses. Increased expression of c-mos RNA was not confined to the lens of the eye but has been detected in any of several tissues tested.     

Monitoring for undertransfusion

BACKGROUND: Most published reviews and audits of blood and blood component transfusion have focused on the issue of overtransfusion and on the inappropriate use of red cell components. There is growing concern that efforts to curb unnecessary transfusions may result in a trend toward undertransfusion of patients. There is little published information that addresses this issue or the magnitude of this practice. STUDY DESIGN AND METHODS: Undertransfusion was evaluated by examining the transfusion records from a 3-month period for 55 patients who met the study criteria of having either a hemoglobin level < 7 g per dL or a platelet count of < 10 × 10(9) per L. If the identified patient did not receive a transfusion within 24 hours of the reported hemoglobin level or platelet count, the medical record was reviewed by a resident physician. RESULTS: A total of 213 individual hemoglobin levels and platelet counts, representing the 55 patients, met our transfusion criteria. All except 8 of the identified patients received red cells and/or platelet transfusions. Reasons for not transfusing red cells included the patient's response to nutritional support and iron supplementation, refusal of blood, and noncompliance. Reasons for not transfusing platelets included falsely low platelet count because of platelet clumping in vitro, contraindication based on clinical diagnosis (e.g., immune thrombocytopenic purpura), and the patient's death before transfusion. CONCLUSION: Red cell and platelet transfusions were appropriately ordered for all patients who met the transfusion criteria. Undertransfusion is not a problem at this institution according to the criteria established. It is recommended that other institutions expand their blood utilization audits to include investigation for evidence of undertransfusion. Further research regarding the issue of undertransfusion is warranted and could be expanded to include other components.     

Circulating insulin inhibits glucagon secretion induced by arginine in type 1 diabetes

OBJECTIVE: To evaluate if insulin has a suppressive effect on the glucagon secretion stimulated by arginine in type 1 diabetes. RESEARCH DESIGN AND METHODS: The alpha-cell response to an i.v. bolus of arginine (150mgkg(-1)) followed by an infusion of arginine (10mgkg(-1)min(-1)) was studied in random order during either low dose infusion (LDT) or high dose infusion (HDT) of insulin in ten patients with type 1 diabetes. The blood glucose level was clamped at an arterialized level of 5mmoll(-1) by a variable infusion of glucose. Venous C-peptide, glucagon, growth hormone, and insulin were analyzed. RESULTS: The mean plasma concentration of insulin was four times higher during the HDT. The C-peptide level did not differ between the LDT and the HDT. During the LDT in response to arginine the blood glucose level increased from 5.0 to 5.8mmol l(-1) although the glucose infusion was markedly reduced, while no change was seen during the HDT. A significantly smaller increase in the glucagon levels during the HDT was seen (area under the curve of 413+/-45 vs 466+/-44pgml(-1)h(-1), P=0.03) while the growth hormone levels were almost identical. CONCLUSION: This study demonstrates that a high level of circulating insulin exerts an inhibitory effect on the glucagon response to arginine in type 1 diabetes. Thus, the suppressive effect of insulin on the glucagon release from the alpha-cell seems to be general and not only dependent on stimulation by hypoglycemia.     

Effects of lead on the heme biosynthetic pathway in rat kidney

Exposure of rats to lead in drinking water at concentrations of 500 ppm and 1000 ppm for 3 and 6 months resulted in elevated blood lead levels, formation of kidney intranuclear inclusion bodies, and increased urinary excretion of uroporphyrin and coproporphyrin. The erythrocytic Zn-protoporphyrin was increased in the highest dose group. No significant effects on body weight gain or kidney weight were observed. Renal activity of delta-aminolevulinic acid synthetase (ALAS) was not significantly affected by lead treatment. The renal activity of delta-aminolevulinic acid dehydrase (ALAD) was moderately increased and ferrochelatase activity was significantly decreased. The relatively small effects of chronic lead exposure on renal heme biosynthesis suggests that intracellular complexation of lead with high-affinity renal lead binding proteins (PbBP) and formation of intranuclear inclusions in proximal tubule cells protects this highly sensitive pathway in kidney from lead inhibition in vivo. These data also suggest that the observed increases in urinary porphyrin excretion are primarily due to lead effects on the erythropoietic system.