Formulation of lyophilized single vial kit of N-N-Ethylene-L-Dicysteine 99m [EC] for labeling with Tc. II: Radiochemical and clinical evaluation 99mr as a renal tubular agent in comparison with Tc-MAG[3]

A Technetium[99m]Tc labeled lyophilized single component kit of N-N-ethylene-I-dicysteine [EC] is developed to replace multiple step kit developed by others. The aim of study is to formulate a radionuclide that is easy to prepare, has rapid plasma clearance, produce high quality images and is an affective alternative to radioiodine labeled orthoiodohippurate, which has been remained the physiological 'gold standard' since long time. To achieve this goal, the systematically varied key parameters such as pH, the use of reducing agents, stabilizers and additives are optimized to obtain maximum radiochemical purity and optimum bio distribution in non human and human primates. Various pH levels of EC showed equally good results in animal experiments but only pH 10 was suitable for human use. Dynamic and renal Scintigraphic studies are carried out with[99m]Tc-EC at pH 8 in 12 volunteers and at pH 10 in 18 volunteers and compared with[99m]Tc-MAG[3], Background ratios, renograms, relative renal function and semi quantitative parameters are available in all studies. The background ratios [mean +/- SD] at 30[th] minute are 0229+/-0.024 and 0.236+/-0.018 for[99m]Tc-EC at pH 10 and[99m]c-MAG[3] respectively. The mean +/- standard error of mean [SEM] values of T[M]X and time to half activity [T[12]] for[99m]Tc-EC [pHIO] are 3.7+/-0.6 and 7.3+/-1.0 respectively while for [99m]Tc-MAG[3], they are 4.0+/-0.8 and 7.9+/-1.4 with p values 0.001 and 0.049 respectively. The values of relative renal function [RRF] for[99m]Tc-EC and[99m]Tc-MAG[3] are 50.8+/-3.11 and 51.2+/-3.4 respectively with p value of 0.822. The residual activity at 25[th] minute [A[25] / A[MAX]] and renal uptake are 0. 209+/-12.67+/-2.80 for[99m]Tc-EC and 0.218+/-0.035 and 1053+/-2.98 for[99m]Tc-MAG[3] [p=0.031 an 0.0003] respectively. The correlation coefficient [R] for T[max], T1/2, A[2]5/A[Max] and renal uptake are 0.96, 0.69, 0.93 and 0.85 respectively

Aged garlic extract and S-allylcysteine prevent apoptotic cell death in a chemical hypoxia model

BACKGROUND: Aged garlic extract (AGE) and its main constituent S-allylcysteine (SAC) are natural antioxidants with protective effects against cerebral ischemia or cancer, events that involve hypoxia stress. Cobalt chloride (CoCl2) has been used to mimic hypoxic conditions through the stabilization of the α subunit of hypoxia inducible factor (HIF-1α) and up-regulation of HIF-1α-dependent genes as well as activation of hypoxic conditions such as reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential and apoptosis. The present study was designed to assess the effect of AGE and SAC on the CoCl2-chemical hypoxia model in PC12 cells. RESULTS: We found that CoCl2 induced the stabilization of HIF-1α and its nuclear localization. CoCl2 produced ROS and apoptotic cell death that depended on hypoxia extent. The treatment with AGE and SAC decreased ROS and protected against CoCl2-induced apoptotic cell death which depended on the CoCl2 concentration and incubation time. SAC or AGE decreased the number of cells in the early and late stages of apoptosis. Interestingly, this protective effect was associated with attenuation in HIF-1α stabilization, activity not previously reported for AGE and SAC. CONCLUSIONS: Obtained results show that AGE and SAC decreased apoptotic CoCl2-induced cell death. This protection occurs by affecting the activity of HIF-1α and supports the use of these natural compounds as a therapeutic alternative for hypoxic conditions

Bucillamine prevents cisplatin-induced ototoxicity through induction of glutathione and antioxidant genes

Bucillamine is used for the treatment of rheumatoid arthritis. This study investigated the protective effects of bucillamine against cisplatin-induced damage in auditory cells, the organ of Corti from postnatal rats (P2) and adult Balb/C mice. Cisplatin increases the catalytic activity of caspase-3 and caspase-8 proteases and the production of free radicals, which were significantly suppressed by pretreatment with bucillamine. Bucillamine induces the intranuclear translocation of Nrf2 and thereby increases the expression of gamma-glutamylcysteine synthetase (gamma-GCS) and glutathione synthetase (GSS), which further induces intracellular antioxidant glutathione (GSH), heme oxygenase 1 (HO-1) and superoxide dismutase 2 (SOD2). However, knockdown studies of HO-1 and SOD2 suggest that the protective effect of bucillamine against cisplatin is independent of the enzymatic activity of HO-1 and SOD. Furthermore, pretreatment with bucillamine protects sensory hair cells on organ of Corti explants from cisplatin-induced cytotoxicity concomitantly with inhibition of caspase-3 activation. The auditory-brainstem-evoked response of cisplatin-injected mice shows marked increases in hearing threshold shifts, which was markedly suppressed by pretreatment with bucillamine in vivo. Taken together, bucillamine protects sensory hair cells from cisplatin through a scavenging effect on itself, as well as the induction of intracellular GSH.

Organic and inorganic selenium compounds produce different protein patterns in the blood plasma of rats

Some selenium compounds offer important health benefits when administered at supranutritional doses, such as improvement of the immune system and of male fertility, and the prevention of some types of cancer. The traditional selenium indexes do not account for the metabolic status of this element among replete individuals. As a consequence, there is a need for new indexes that distinguish between repletion statuses of selenium. The aim of this work was to indentify some plasmatic proteins that respond to supranutritional doses of selenium, which could be proposed as new protein markers of selenium intake. The effect on rats of dietary supplementation with either selenomethylselenocysteine (SMSeC) or sodium-selenate on some blood plasma proteins was investigated. Two experimental groups consisting of six rats each were fed a basic diet supplemented with either SMSeC or sodium-selenate at 1.9 mg-Se / g-diet for ten weeks. The control group was fed a diet that contained the recommended selenium dose (0.15 mg-Se / g-diet). The changes in the abundance of a group of plasmatic proteins were quantified and analysed statistically. Haptoglobin, apolipoprotein E and transthyretin increased their abundance after diet supplementation with either form of selenium. HNF6 was responsive only to SMSeC, whereas fibrinogen responded only to sodium-selenate. We postulate that the protein patterns observed in this work could be proposed as new molecular biology-based markers of selenium intake.

Memória de procedimentos e SPECT cerebral: avaliação de fluxo sanguíneo cerebelar e em córtex pré-frontal durante uma tarefa visuo-motora / Procedural memory and brain SPECT: blood flow evaluation in the cerebellum and pre-frontal cortex during a visuo-motor task

O objetivo deste estudo foi avaliar o fluxo sanguíneo cerebral no córtex cerebelar (4 sub-regiões) e no córtex pré-frontal, em repouso e durante uma tarefa motora. A amostra foi composta por 8 sujeitos saudáveis, ambos os sexos, entre 23 e 36 anos. O grupo foi submetido a tarefa visuo-motora (memória implícita) que consistia na ação de desviar um submarino de supostas minas que percorriam a tela do monitor. Para avaliar a perfusão, foi utilizado o método de análise semi-quantitativa para imagens de SPECT cerebral - 99mTc-ECD. Os resultados evidenciaram aumento de atividade nas áreas de interesse durante a realização da tarefa. Em conclusão, quatro sub-regiões do córtex cerebelar e ambos os hemisférios do córtex pré-frontal apontaram uma ativação simultânea durante a tarefa. Ainda, e conforme estudos prévios, nossos resultados sugerem um modo de operação em paralelo do sistema nervoso central, no intuito de integrar uma informação sensorial e motora.

The objective of the present study was to evaluate the cerebral blood flow in the cerebellar (4 sub-regions) and pre-frontal cortex, when subjects were in rest and during a motor task performance. The sample consisted of 8 healthy subjects, male or female, between 23 and 36 of age. The visuo-motor task _ implicit memory _ requires the subjects to navigate and swerve a graphic submarine from missiles that run on the screen. Semi-quantitative analysis with brain SPECT (99mTc-ECD) was used to evaluate regional perfusion. The results revealed an increased activity in all areas of interest during motor task. In conclusion, four sub-regions of cerebellar cortex and both pre-frontal hemispheres showed a simultaneous activation during task. Moreover, our findings suggest as seen in previous experiments that the central nervous system operates in a parallel fashion, in order to integrate sensory and motor information.

Assessment of Cerebrovascular Reserve before and after STA-MCA Bypass Surgery by SPECT and SPM Analysis

OBJECTIVE: The purpose of this study was to objectively assess the efficacy of superficial temporal artery to middle cerebral artery (STA-MCA) bypass surgery using Technetium (Tc)-99m-ethyl cysteinate dimer (ECD) single photon emission computed tomography (SPECT) in patients who underwent STA-MCA bypass surgery. MATERIALS AND METHODS: Brain perfusion SPECT images obtained at baseline and after the administration of acetazolamide were reconstructed using statistical parametric mapping in 23 patients, both before and after STA-MCA bypass surgery. The clinical outcomes of the surgery were also recorded and compared with the hemodynamic changes. A voxel with an uncorrected p-value of less than 0.001 was considered to be statistically significant. RESULTS: SPECT images of the territory supplied by the bypass graft showed an increase in both cerebrovascular flow and reserve at baseline, and the increase was significantly higher following the administration of acetazolamide. All patients showed improvement of clinical symptoms and increased blood flow to the left temporal, parietal, and frontal cortices as well as the thalamus. CONCLUSION: Brain SPECT effectively and objectively demonstrated the improved outcomes of STA-MCA bypass surgery, and thus may be used in postoperative analyses.

Patterns of single photon emission tomography (SPECT) among patients with dementia in the memory clinic at Siriraj Hospital.

OBJECTIVE: The authors hypothesized that there is a pattern difference in cerebralperfusion of the 99-Technitium L, L-ethyl cysteinate dimer Single Photon Emission Computer Tomography (99-Tc ECD SPECT) between mild and moderate to severe dementia. MATERIAL AND METHOD: The authors reported a retrospective study in the Memory Clinic, Siriraj Hospital between January 2001 and October 2003 including only patients with Alzheimer's disease, vascular dementia, and mixed dementia. Clinical dementia rating (CDR) was used to document dementia severity. Patterns of hypoperfusion were classified into no definite hypoperfusion, regional hypoperfusion, and diffused hypoperfusion. RESULTS: One hundred and seven patients were included in the present study. Only mean Thai Mental State Examination (TMSE) score was different between the two groups. There was no significant correlation between pattern of hypoperfusion in brain SPECT and severity of dementia. CONCLUSION: The authors cannot demonstrate the pattern of hypoperfusion of 99-Tc ECD SPECT among patients' difference in dementia severity.

Ethylenedicysteine versus diethylenetriamine pentaacetic acid as the carrier of technetium Tc 99m in diuretic renography for patients with upper urinary tract obstruction

L,L-ethylenedicysteine [EC] is a new carrier of technetium Tc 99m [99mTc] with a lower affinity to plasma albumin in comparison with diethylenetriamine pentaacetic acid [DTPA]. We compared 99mTc-EC scan with 99mTc-DTPA scan in diuretic renography for patients with obstructive uropathy. Thirty-three patients with upper urinary tract obstruction were randomly selected and underwent diuretic renographies by 99mTc-EC and 99mTc-DTPA. The counts of radioisotope per pixel in the target [the kidney] and background tissues as well as the clearance half-life of these two radiopharmaceuticals were measured and compared. Mean counts of radioisotope per pixel in the target tissue was not different between 99mTc-EC and 99mTc-DTPA scans, but in the background tissue, it was less for 99mTc-EC [P =.003]. Target-background ratio was higher for 99mTc-EC scan [3.80 +/- 2.11 versus 2.48 +/- 1.39; P <.001]. Renal clearance half-life of radioisotope was shorter for 99mTc-EC scan than 99mTc-DTPA scan [58.15 +/- 15.17 minutes versus 78.65 +/- 19.99 minutes; P =.033]. The results were similar for uremic patients [with a serum creatinine level > 2mg/dL]. Target-background ratio of radiopharmaceutical uptake rates in diuretic renography was a good indicator of the higher resolution of 99mTc-EC than 99mTc-DTPA scan. We also demonstrated the faster clearance of 99mTc-EC than 99mTc-DTPA. This results in less radiation that is especially useful in children. To our opinion, 99mTc-EC can better depict the kidneys in comparison with 99mTc-DTPA

Antidiabetic and antioxidant effects of S-methyl cysteine sulfoxide isolated from onions (Allium cepa Linn) as compared to standard drugs in alloxan diabetic rats.

Antidiabetic and antoxidant effects of S-methyl cysteine sulfoxide (SMCS) isolated from A. cepa and two standard drugs, glibenclamide and insulin were studied and compared in alloxan diabetic rats after using each of them for treatment for two months. These drugs ameliorated the diabetic condition significantly, viz. maintenance of body weight and control of blood sugar in rats. Further they lowered the levels of malondialdehyde, hydroperoxide and conjugated dienes in tissues exhibiting antioxidant effect on lipid peroxidation in experimental diabetes. This is achieved by their stimulating effects on glucose utilization and the antioxidant enzymes, viz. superoxide dismutase and catalase. The probable mechanism of action of SMCS and glibenclamide may be partly dependent on the stimulation of insulin secretions and partly due to their individual actions. In the amelioration of diabetes the standard drugs showed a better action, but as an antioxidant SMCS proved to be a better one.

Tc-99m-ECD SPECT Brain Imaging in Children with Tourette's Syndrome

We undertook this study to assess the patterns of regional cerebral perfusion (RCP) with SPECT using Technetium-99m-ethyl cysteinate dimer (Tc-99m-ECD) in children with Tourette's Syndrome (TS), and to compare these with the patterns in a group of normal controls. The study sample consisted of 38 children (7 to 14 years) who met the ICD-10 and DSM/IV criteria for Tourette's Syndrome, and a control group of 18 children (9 to 14 years). The Children's Depression Inventory and Maudsley Obsessional-Compulsive Questionnaire were used for assessment, and the severity of motor and vocal tics were assessed using the Goetz Rating Scale. The RCP values were significantly lower in the TS group in left caudate, cingulum, right cerebellum, left dorsolateral prefrontal, and the left orbital frontal region. A positive correlation was found between the severity of vocal tics and blood flow of mid-cerebellum, right dorsolateral prefrontal and left dorsolateral prefrontal regions. Although no depressive or obsessive patients were included in the study, the depression and obsession scores were found to be negatively correlated with all RCP values, especially in the temporal regions. Further studies are needed to explore the relationship between the hypoperfusion of certain brain areas and the underlying neurophysiology and neurobiology of patients with TS. Additional disturbances such as obsessive- compulsive symptoms and depressive symptoms should also be assessed.

Significance of 99mTc-ECD SPECT in Acute and Subacute Ischemic Stroke: Comparison with MR Images Including Diffusion and Perfusion Weighted Images

99mTc-ECD SPECT is valuable for the evaluation of cell viability and function. The purpose of the present study was to evaluate the significance of 99mTc-ECD brain SPECT in ischemic stroke. We compared 99mTc-ECD brain SPECT with perfusion and diffusion weighted images (PWI, DWI). Ten patients with acute and early subacute ischemic stroke were included in this prospective study. T2-weighted images (T2WI), DWI, PWI and 99mTc-ECD SPECT were obtained during both the acute/early subacute and late subacute stages. In the case of PWI, time to peak (TTP) and regional cerebral blood volume (rCBV) maps were obtained. The rCBV map and 99mTc-ECD SPECT images were compared in 8 lesions using delta AI. The asymmetry index (AI) was calculated as (Ci - Cc) X 200 / (Ci + Cc); where Ci is the mean number of pixel counts of an ipsilateral lesion and Cc is the mean number of pixel counts of the normal contralateral hemisphere. delta AI was defined as AIacute - AIsubacute in the ischemic core and periphery. PWI and 99mTc-ECD SPECT detected new lesions of the hyperacute stage or of evolving stroke more accurately than T2WI and DWI. 99mTc-ECD SPECT was able to localize the infarct core and peri-infarct ischemia in all lesions in both the acute and the subacute stages. delta AI was higher in the rCBV map than in the 99mTc-ECD SPECT images in the ischemic core (p = 0.063) and in the periphery (p = 0.091). In the 99mTc-ECD SPECT images, delta AI was higher in the ischemic core than in the periphery (p = 0.028). During the subacute stage, 99mTc-ECD SPECT detected all the lesions without the pseudonormalization seen in the MR images of 5/11 lesions. Based on this study, 99mTc-ECD SPECT is comparable to PWI in terms of its ability to detect acute stroke and is more useful than PWI in the case of subacute infarction.

A Case of BOOP Developed during Bucillamine Treatment for Rheumatoid

We describe a patient with rheumatoid arthritis(RA) who developed bronchiolitis obliterans organizing pneumonia(BOOP) during the treatment of bucillamine. A 51 year-old man was admitted to the hospital for an abnormal shadow on his chest radiogragh. He had been diagnosed as having RA 3 years previously and had been receiving 200 mg of bucillamine for 21 months. Two months prior to admission, he presented with a cough and his chest X-ray showed opacities in both lower lungs. He was treated with antibiotics for 2 months after the development of cough and lesions on the chest X-ray, but the symptoms and lung lesions became more aggravated. On admission, an HRCT revealed airspace consolidations in the subpleural space of both basal lungs and a CT-guided fine needle aspiration biopsy showed Masson's body filling air space, interstitial infiltration of acute and chronic inflammatory cells and type II cell hyperplasia, consistent with BOOP. Bucillamine was stopped and 50 mg of prednisolone was administered. His symptoms and infiltrations on the chest X-ray resolved. We suggest that bucillamine should be considered as a drug possibly associated with BOOP.

Effects of S-allyl cysteine sulfoxide isolated from Allium sativum Linn and gugulipid on some enzymes and fecal excretions of bile acids and sterols in cholesterol fed rats.

S-allyl cysteine sulfoxide, isolated from garlic, A. sativum, is more or less as active as gugulipid in controlling hypercholestermia, obesity and derangement of enzyme activities in cholesterol diet fed rats. The beneficial effects of the drugs are partly due to their inhibitory effects on transaminases, alkaline phosphatase, lipogenic enzymes and HMG CoA reductase and partly due to their stimulatory effects on plasma lecithin-cholesterol acyl transferase lipolytic enzymes and fecal excretion of sterols and bile acids.

Antiperoxide effects of S-allyl cysteine sulphoxide isolated from Allium sativum Linn and gugulipid in cholesterol diet fed rats.

Cholesterol containing diet significantly increased not only the body weight, but also the weight of liver and adipose tissue of rats. This is accompanied by a significant increase in blood lipids, atherogenic index and lipid peroxidation and a significant decrease in reduced glutathione level, superoxide dismutase and catalase activities in tissues. Treatment with S-allyl cysteine sulphoxide reverses the deleterious effects of cholesterol diet significantly and almost as effectively as gugulipid.

Antidiabetic and hypolipidemic effects of S-methyl cysteine sulfoxide isolated from Allium cepa Linn.

S-methyl cysteine sulphoxide (SMCS), a sulphur containing amino acid isolated from onion (Allium cepa Linn) showed antidiabetic and antihyperlipidemic effects. Oral administration of SMCS daily at a dose of 200 mg/kg body weight for a period of 45 days to alloxan diabetic rats controlled significantly their blood glucose and lipids in serum and tissues and altered the activities of liver hexokinase, glucose 6-phosphatase and HMG CoA reductase towards normal. The above effects of SMCS were comparable to those of glibenclamide and insulin.

Antidiabetic effects of S-allyl cysteine sulphoxide isolated from garlic Allium sativum Linn.

S-allyl cysteine sulphoxide (SACS), a sulphur containing amino acid of garlic which is the precursor of allicin and garlic oil, has been found to show significant antidiabetic effects in alloxan diabetic rats. Administration of it at a dose of 200 mg/kg body weight decreased significantly the concentration of serum lipids, blood glucose and activities of serum enzymes like alkaline phosphatase, acid phosphatase and lactate dehydrogenase and liver glucose-6-phosphatase. It increased significantly liver and intestinal HMG CoA reductase activity and liver hexokinase activity.