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.     

Flexible tantalum stents implanted in aortas and iliac arteries: effects in normal canines

Vascular endoprostheses made of knitted tantalum wire and expanded over angioplasty balloons were placed into aortas or iliac arteries of 14 normal dogs. Twelve stents were placed into the infrarenal abdominal aorta and two stents in the left common iliac arteries by the left carotid artery approach. To firmly expand the stent against the vascular wall, nominal stent sizes 0.5-1.0 mm larger than the measured arterial diameter were required. Arteriography performed at specified follow-up intervals showed no evidence of thrombi or emboli; all side branches (lumbar arteries) covered by the stents remained patent. Vascular diameter decreased minimally at 8 and 26 weeks, associated with histopathologic evidence of neointimal buildup. This buildup was highest at 8 weeks (mean, 313 microns) and was slightly less at 26 weeks (mean, 223 microns). Almost complete coverage by endothelium was seen as early as 3 weeks. It is concluded that the flexible tantalum wire stents are well tolerated by the arterial wall and become quickly endothelialized. No excessive neointimal buildup was observed during the 6-month study.     

False-positive results in the detection of anti-LAV/HTLV-III antibodies by enzyme immunoassay

Two groups of sera were investigated with two different enzyme immunoassays for the detection of anti-LAV/HTLV-III-antibodies: 50 sera collected from patients with lupus erythematosus and 5 sera containing anti-HLA-DR4 antibodies. Of the 50 sera of the lupus erythematosus patients, 2 were positive in each of the tests. Of the 5 sera that contained anti-HLA-DR4 antibodies, one was positive. In addition, 11 sera showed positive results after heat treatment (56 degrees C, 1 h) in one of the tests. However, all sera in this group gave negative results in the other test. The positive results could not be confirmed with the immunoblot. These findings show that one must be aware of false-positive results when the sera of certain types of patients are investigated in anti-LAV/HTLV-III enzyme immunoassays. The sera of patients with lupus erythematosus, as well as that of polytransfused persons or multiparous women, that have been sensitized with HLA-DR4 antigens; heat treatment in one test has an effect on sera.     

Consensus of microbiology reporting of ear swab results to primary care clinicians in patients with otitis externa

Otitis externa is a ubiquitous inflammatory disease; although it arises most commonly from an infection, there is no consensus in the UK for the reporting of ear swab culture results. This study aims to review current microbiology laboratory reporting of ear swab specimens to primary care and reach an evidence-based consensus for a reporting policy. Fifty consecutive ear swab reports were reviewed from each of 12 laboratories in the South West region to determine and discuss reporting practice. The Health Protection Agency (HPA) GP Microbiology Laboratory Use Group reviewed the underlying evidence and worked towards a consensus of expert microbiology opinion for laboratory reporting of ear swab results using a modified version of the Delphi technique. A total of 487 reports from primary care were reviewed (54% female; 46% male). Cultures most commonly yielded Pseudomonas species (36%), Staphylococcus species (21%), Streptococcus species (15%) and fungi (11%). Five reporting policies were agreed: Policy 1: Common pathogens such as group A beta-haemolytic streptococci, Streptococcus pneumoniae, Staphylococcus aureus - Always reported by name with antibiotic susceptibilities. Policy 2: Pseudomonas species - Always reported, but antibiotic susceptibilities only reported in severe disease. Policy 3: Aspergillus, Candida, coliforms and Proteus species, as well as non-group A streptococci and anaerobes - Only reported if moderate numbers of colonies and it is the predominant organism present; if appropriate report antibiotic susceptibilities. Policy 4: Coagulase-negative staphylococci, diphtheroids and enterococci - Not reported by name; generic terms used and antibiotic susceptibilities not reported. Policy 5: When antibiotic susceptibilities reported these must include susceptibility to a topical antibiotic. It is suggested that laboratories should consider adopting this evidence-based reporting consensus for ear swab culture results from primary care patients with otitis externa.     

Spontaneous gastric rupture in the newborn: a clinical review of nineteen cases.

The term "spontaneous gastric rupture" is used to describe our cases of neonatal gastric perforation. Nineteen such neonates are reviewed. Current opinions regarding the possible etiology is included in the discussion. Neonatal asphyxia was the most commonly seen predisposing cause in our series (63%). Roentgenograms of the abdomen are most helpful in making a positive diagnosis. Surgical repair is the treatment of choice. All the surviving patients in our series underwent surgical repair. The need for gastrostomy during surgery should be individualized. The mortality was 27% in the cases operated since 1970; a significant improvement as compared to a mortality rate of 62% for the cases operated before 1970.     

老年人血浆溶血磷脂酸和磷脂酸水平综合干预后的效果比较

目的:通过对老年人进行血浆溶血磷脂酸和磷脂酸的筛检,从而认识血浆溶血磷脂酸和磷脂酸在血栓预防中的作用。方法:对2004-04/07期间的1657名和2005-04/07期间的1748名离休干部进行血浆溶血磷脂酸和磷脂酸含量测定,并对溶血磷脂酸>3.0μmol/L和磷脂酸>5.0μmol/L的阳性人员进行药物干预。同时,选择2004年溶血磷脂酸和/或磷脂酸阳性人员119人,随机分为两组:①干预组(n=72):男63人,女9人,平均年龄78岁。口服阿司匹林100mg/d,持续1个月。②对照组(n=47):男42人,女5人,平均年龄76岁。干预后,测定两组血浆中溶血磷脂酸和磷脂酸的含量。结果:纳入对象全部进入结果分析。2005年磷脂酸及血浆溶血磷脂酸 磷脂酸阳性率均明显低于2004年(P<0.01),尤其是磷脂酸的阳性率降低的更为明显。2005年血浆溶血磷脂酸和磷脂酸的平均值均明显低于2004年(P<0.01)。干预组干预后血浆溶血磷脂酸和磷脂酸明显低于干预前及对照组(P<0.01)。结论:①血浆溶血磷脂酸和磷脂酸的测定可作为血栓预警和了解抗血栓药物疗效的一种手段。②阿司匹林干预后,血浆溶血磷脂酸和磷脂酸的含量均降低,可作为一种降低缺血性疾病发生率的有效途径。