Development of a high performance zinc-62/copper-62 radionuclide generator for positron emission tomography

Clinical utilisation of positron emission tomography could be enhanced by the availability of shortlived radionuclides derived from generator systems. The zinc-62/copper-62 combination is one such system which could be used as a source for a number of copper-62 radiopharmaceuticals. We have developed and optimised a high activity (5.6 GBq, 150 mCi) zinc-62/copper-62 generator to provide ⁶²CU in a form that is suitable for direct labelling of pyruvaldehyde-bis-(N ⁴-methylthiosemicarbazone)-copper(II), Cu(PTSM). The distribution coefficients of Zn(II) and Cu(II) between anion-exchange resin and various hydrochloric acid/organic solvent mixtures were measured. Based on these measurements a generator eluent of 0.3 M HCl/40% ethanol provided ⁶²CU in >90% yield in a 3-ml volume. A very low ⁶²Zn breakthrough of less than 3×10^–7% was achieved. Copper-PTSM was successfully labelled with the no-carrier-added ⁶²Cu eluent directly from the generator with 94% radiochemical yield. Offprint requests to: J. Zweit, The Royal Marsden Hospital     

Kinetics of penetration of common antiepileptic drugs into cerebrospinal fluid

The rate of entry of common antiepileptic drugs and some active metabolites into cerebrospinal fluid (CSF) was studied in anesthetized dogs from which blood and CSF samples were withdrawn at short intervals. Diazepam, its active metabolites desmethyldiazepam and oxazepam, clonazepam, and ethosuximide entered the CSF very rapidly with mean half-times to equilibrium between 3 and 7 min. Valproic acid, phenytoin, phenobarbital, and carbamazepine went in more slowly, but mean penetration half-times were still only 12-18 min. Primidone, its metabolite phenylethylmalondiamide , and the active metabolite of carbamazepine, i.e., carbamazepine-10,11-epoxide, passed into CSF considerably slower, with half-times of 40-50 min. In order to evaluate to what extent physicochemical properties determine the penetration rates of antiepileptic drugs into the CSF, three factors were examined: the degree of ionization of the respective drugs at physiologic pH, the plasma protein binding, and the lipid-solubility, measured by organic solvent/buffer distribution ratios. Ionization was not considered as a rate-limiting factor, because all compounds except valproic acid were highly non-ionized at pH 7.4. No correlation was found between penetration rates and plasma protein binding, but at equilibrium, the ratio between CSF and total plasma concentrations was almost equal to the free fraction of drug in plasma. A significant correlation was found between penetration rate and the benzene/buffer distribution ratio of antiepileptic drugs, which indicates that the lipid-solubility, rather than the protein binding or the degree of ionization, plays the major role in determining the differences in rate of entry of these drugs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Radionuclide angiographic and echocardiographic quantitation of left-to-right shunts in children with ventricular septal defect

Summary Pulmonary to systemic blood flow ratios (Qp:Qs) were estimated in 16 children with ventricular septal defects using simultaneous echocardiography and radionuclide angiography, and compared to Qp:Qs measured at cardiac catheterization by the Fick principle method (Fick). When ratios of echographic left atrial dimensions (LAD) to body surface area (LAD/M²), body length (LAD/ht), and aortic root diameter (LAD/Ao) were compared to the Qp:Qs determined by Fick, the correlation coefficients were r=0.70 for LAD/M², r=0.66 for LAD/ht, and r=0.54 for LAD/Ao. The correlation coefficients between Qp:Qs by Fick, and left ventricular dimensions/M² and fractional shortening of the left ventricle were not significant. The correlation coefficients between Qp:Qs and the ratios estimated by gamma-variate and area-ratio analysis of radioisotope pulmonary dilution curves were r=0.92 and r=0.84, respectively. Thus, radionuclide angiography provided more accurate quantitation of left to right shunting through a ventricular septal defect than echocardiography. However, difficulty in obtaining adequate bolus injections of the radioisotope may result in technical failures whereas echocardiographic measurement is possible in almost all pediatric patients. Finally, the gamma-variate method cannot accurately quantitate shunt ratios greater than 3.5 to 1.Supported in part by USPHS Grant Nos. 1-T32HL07417-01 and 5-T01HL05728-09 and American Heart Association Southwest Ohio Chapter     

131I-层粘连九肽的合成及在荷乳腺癌裸鼠中的显像和分布

目的用１３１Ｉ层粘连九肽进行荷乳腺癌裸鼠的肿瘤受体显像及其生物分布研究。方法以固相法合成层粘连九肽，经ＨＰＬＣ纯化，用氯胺Ｔ法进行１３１Ｉ标记。标记物以ＳｅｐｈａｄｅｘＧ１０纯化。尾静脉注入荷乳腺癌裸鼠体内，分别在１、２、３、４、５、６小时进行肿瘤显像，划出感兴趣区，测其Ｔ／Ｂ值。静脉给药后分别在３、６小时观察生物分布，计算其每克组织摄取注射剂量百分数（％ＩＤ／ｇ）和肿瘤与非肿瘤的放射性比值（Ｔ／ＮＴ值）。结果化学合成的层粘连九肽经ＨＰＬＣ、ＦＡＢＭＳ纯化鉴定，Ｍ＋１＝９６６３。尾静脉注射后４～５小时肿瘤部位有明显浓聚，Ｔ／Ｂ值达４６２。肿瘤／肌肉的Ｔ／ＮＴ值在６小时为３４５。结论１３１Ｉ层粘连九肽有希望用于诊断人体乳腺癌     

Peak B endorphin concentration in cerebrospinal fluid: reduced in chronic pain patients and increased during the placebo response

The level of an endogenous opioid (peak B endorphin) was measured in chromatographically fractionated cerebrospinal fluid (CSF) sampled from two groups of chronic pain patients before and after intrathecal saline (placebo) injection. As assessed by a verbal rating scale, one group reported no change in their level of pain (non-responders, NR;n=6) while the other group reported complete or >50% pain relief (placebo responders, PR;n=14). We find, as has been reported previously, that initial peak B levels were lower (by 50%) in these chronic pain patients' CSF than in CSF from pain-free (PF) normal controls (P<0.001,t-test). Peak B levels measured from CSF of the NR group undergoing this procedure did not change (P>0.4, pairedt-test). In contrast, a significant 2.3-fold increase was measured in the CSF peak B level of the PR group (P<0.05, pairedt-test). This is the first direct evidence that a CSF opioid is correlated with placebo pain relief in chronic pain patients. Peak B is a potent analgesic substance when administered by the intracerebroventricular route in mice and its level is related to the patients' pain status in a presumably causal manner.     

Decreased soluble interleukin-6 receptor in cerebrospinal fluid of patients with Alzheimer''s disease

The function of the cytokine interleukin-6 (IL-6) is augmented by soluble IL-6 receptors (sIL-6R). We investigated cerebrospinal fluid sIL-6R concentrations in patients with Alzheimer's disease (AD) compared to age-matched healthy subjects and individuals with at least one first degree relative with AD. We found a statistically significant decrease in sIL-6R levels in the AD group compared to controls. Complete analysis of the IL-6R complex seems crucial to better understand the impact of IL-6 in AD pathophysiology.     

Cerebrospinal fluid analyses in migraine patients and controls

To investigate the role of central neurotransmitters in the pathogenesis of migraine, we measured cerebrospinal fluid (CSF) levels of certain amino acids (glycine, taurine, glutamine) and metabolites of biogenic amines (5-hydroxyindoleacetic acid and homovanillic acid) in 38 migraine patients and compared them with the levels from 10 headache-free controls. The levels of taurine, glycine and glutamine were significantly higher in the migraine patients (p < 0.0001 for taurine and glycine; p < 0.0009 for glutamine); there were no significant differences among the three migraine subgroups (infrequent migraine, frequent migraine and transformed migraine). In seven patients subsequently treated with divalproex sodium, CSF taurine levels decreased significantly from pretreatment baseline values. These data support the concept that migraine is at least in part a disorder of central neurotransmission.     

Cerebrospinal fluid shunt valve fracture with separation: report of three cases

Three cases of shunt valve fracture with separation are reported. Fracture with separation of the shunt valve of a cerebrospinal fluid shunt is an infrequent occurrence. Because a portion of the shunt valve is radiolucent on a shunt survey radiograph, this problem is easily overlooked if it occurs. The diagnosis can be made by comparing old and new shunt survey radiographs and noting the increased distance between radiopaque portions of the shunt on the new X-ray films.     

Release from live choroid plexus of apical fragments and electrophoretic characterization of their synthetic products

Protein synthesis and secretion by the choroid plexus (CP) has been implicated as a major source of certain proteins in cerebrospinal fluid (CSF), such as transthyretin. The suggestion that proteins are elaborated from CP through apocrine secretion has been borne out by the presence of newly labeled proteins in apical protrusions from CP (Agnew et al.: Cell and Tissue Research 208:261-281, 1980a). When the protrusions (aposomes) separate from the cells, they continue to incorporate labeled amino acids (Gudeman et al.: Tissue and Cell 19:101-109, 1987). In the present work the formation of aposomes in live CP explants indicated that these spheroids were not the result of fixation. Aposomes were also identified within rat CSF by immunohistochemistry with monoclonal directed against aposomes as well as with anti-transthyretin serum. The protein product of aposomes was characterized by 2-dimensional SDS-PAGE and compared to the protein products of whole CP tissue. Paradoxically, transthyretin, a heavily labeled protein in the tissue, was virtually undetected in the aposome synthetic profile. However, four other proteins were expressed in relatively equivalent amounts by the aposomes. The presence of mRNA in aposomes was detected with a poly dT probe, and the presence of actin was revealed by phalloidin staining of aposomes. These studies provide a more comprehensive definition of aposomes, but the functions of their secreted proteins remains to be determined.     

Design of Pusher-Plate-Type Left Ventricular Assist Device Based on Mechanical Analyses

A permanently implantable left ventricular assist device (LVAD) pump of the pusher-plate type was designed based on mechanical analyses. A series of three different segmented polyether polyurethanes was utilized for the diaphragm, cannulae, and their blood-contacting surfaces, considering each material's characteristics. The span and thickness of the pump diaphragm were determined so as to minimize the stress developed by the bending and blood pressure forces. The inflow and outflow cannulae were designed using fundamental equations that describe the operation of a piston-type reciprocating pump. The pump diameter was determined considering the required flow for the average Japanese person. In vitro and in vivo experiments showed good pump performance, which satisfied the design specifications. No failure was observed in the designed diaphragm. The Hall effect sensor incorporated in the pump was very useful in monitoring the cardiac output of the pump.