Usefulness of Ictal and Interictal 99mTC Ethyl Cysteinate Dimer Single Photon Emission Computed Tomography in Patients with Refractory Partial Epilepsy

Summary: Purpose: Ictal perfusion single photon emission computed tomography (SPECT), using HMPAO, has been shown to localize epileptic foci in ～90% of studies. Unfortunately, HMPAO decomposes rapidly, precluding the performance of ictal studies. Ethyl cysteinate dimer (ECD) is a SPECT perfusion agent recently approved by the Food and Drug Administration. After preparation, this compound is stable for ～6 h. facilitating the performance of ictal studies. Methods: In a prospective, open-label, uncontrolled, non randomized study, we evaluated the potential benefits of the use of ^99mTc-ECD SPECT for lateralization of the epileptic focus. Ten consecutive adult epilepsy surgery candidates were studied with ictal and interictal ^99mTc-ECD SPECT. Results: The mean delay between seizure onset and ictal SPECT injection was 23.2 s. The mean seizure duration was 84.1 s. Ictal studies agreement between the epilepsy focus and area of hyperperfusion was evident in 8 of 10 cases. In one case, SPECT was lateralized in a patient with bilateral temporal lobe epilepsy (TLE); however, hyperperfusion was observed on the same side of that particular seizure. In another case, there was location disagreement. Interictal SPECT showed focal hypoperfusion in three cases. Conclusions: ^99mTc-ECD proved to be an optimal tracer for ictal studies. Although this is a small series, the results of ictal and interictal findings using 99mTc-ECD are similar to those reported with ^99mTc-HMPA0. Because ^99mTc-ECD has a longer decomposition time, true ictal studies are easier to obtain. This new tracer will probably allow the use of ictal SPECT to become widely accepted in most epilepsy centers.     

Catecholamine synthesis and metabolism in the central nervous system of mice lacking α2-adrenoceptor subtypes

Background and purpose:

This study investigates the role of α₂-adrenoceptor subtypes, α_2A, α_2B and α_2C, on catecholamine synthesis and catabolism in the central nervous system of mice.

Experimental approach:

Activities of the main catecholamine synthetic and catabolic enzymes were determined in whole brains obtained from α_2A-, α_2B- and α_2C-adrenoceptor knockout (KO) and C56Bl\7 wild-type (WT) mice.

Key results:

Although no significant differences were found in tyrosine hydroxylase activity and expression, brain tissue levels of 3,4-dihydroxyphenylalanine were threefold higher in α_2A- and α_2C-adrenoceptor KO mice. Brain tissue levels of dopamine and noradrenaline were significantly higher in α_2A and α_2CKOs compared with WT [WT: 2.8 ± 0.5, 1.1 ± 0.1; α_2AKO: 6.9 ± 0.7, 1.9 ± 0.1; α_2BKO: 2.3 ± 0.2, 1.0 ± 0.1; α_2CKO: 4.6 ± 0.8, 1.5 ± 0.2 nmol·(g tissue)⁻¹, for dopamine and noradrenaline respectively]. Aromatic L-amino acid decarboxylase activity was significantly higher in α_2A and α_2CKO [WT: 40 ± 1; α_2A: 77 ± 2; α_2B: 40 ± 1; α_2C: 50 ± 1, maximum velocity (V_max) in nmol·(mg protein)⁻¹·h⁻¹], but no significant differences were found in dopamine β-hydroxylase. Of the catabolic enzymes, catechol-O-methyltransferase enzyme activity was significantly higher in all three α₂KO mice [WT: 2.0 ± 0.0; α_2A: 2.4 ± 0.1; α_2B: 2.2 ± 0.0; α_2C: 2.2 ± 0.0 nmol·(mg protein)⁻¹·h⁻¹], but no significant differences were found in monoamine oxidase activity between all α₂KOs and WT mice.

Conclusions and implications:

In mouse brain, deletion of α_2A- or α_2C-adrenoceptors increased cerebral aromatic L-amino acid decarboxylase activity and catecholamine tissue levels. Deletion of any α₂-adrenoceptor subtypes resulted in increased activity of catechol-O-methyltransferase. Higher 3,4-dihydroxyphenylalanine tissue levels in α_2A and α_2CKO mice could be explained by increased 3,4-dihydroxyphenylalanine transport.     

Effect of tecarfarin,a novel vitamin K epoxide reductase inhibitor,on coagulation in beagle dogs

Background and purpose:

Tecarfarin (ATI-5923) is a novel vitamin K epoxide reductase inhibitor that is metabolized by esterase (mainly human carboxylesterase 2) to a single major metabolite, ATI-5900, in rats, dogs and humans. Tecarfarin is not significantly metabolized by CYP450 enzymes. The objective of this study was to test and compare the efficacy of tecarfarin with that of warfarin, when administered either intravenously or once a day orally, to produce stable anticoagulation in beagle dogs.

Experimental approach:

Effects on coagulation were assessed by measuring the activity levels of Factor VII and Factor X and thromboplastin-induced coagulation times, reported as prothrombin time (PT).

Key results:

Continuous intravenous infusions and oral administration of tecarfarin and warfarin caused a dose-dependent decrease in activity of Factor VII and Factor X, and associated increase in PT. Intravenous fresh frozen canine plasma or subcutaneous vitamin K₁ treatment reversed the anticoagulant effects of orally administered tecarfarin. Consistent with the inhibitory effects of amiodarone on CYP2C9, co-administration of amiodarone significantly increased the anticoagulation effect of warfarin and plasma warfarin concentrations. In contrast, amiodarone had no effect on the anticoagulation induced by tecarfarin or tecarfarin plasma concentrations in this model.

Conclusions and implications:

Overall, the data presented herein indicate that tecarfarin, via a vitamin K-dependent mechanism, causes changes in key parameters of haemostasis in beagle dogs that are consistent with effective anticoagulation. Compared to warfarin it has a decreased potential to interact metabolically with drugs that inhibit CYP450 enzymes and, therefore, may offer an improved safety profile for patients.     

Antiparkinsonian activity and behavioural effects of newer quinazolinones

Sixteen new compounds 2-methylamino substituted phenyl-3-substituted anilino 4 (3H) quinazolinones (3-18) were prepared. All the compounds were evaluated for their antiparkinsonian activity and compared with bromocriptine. Compounds 10,15 and 18 showed better activity. These compounds also bind with the dopamine receptors in striatal membrane preparations of rat brain.     

Investigation in tea on fate of fenazaquin residue and its transfer in brew.

Fenazaquin is a non-systemic acaricide/insecticide used widely in controlling mites and other related pests in fruits, vegetables and tea. The objective of this research was to investigate the disappearance trend in tea of fenazaquin residue level and its transfer in brew. Fenazaquin was applied on a tea crop at two rates, 125 and 250 g AI/ha in wet and dry seasons under field conditions. Samples (green shoots, made tea and its brew) were analyzed for fenazaquin and quantification was by high performance liquid chromatography using a UV detector. The residue dissipated faster in the wet season than in the dry season. Seven days after the treatment (normal round of plucking) the residues observed in the green shoots at the two rates were 2.17, 3.07 mg/kg and 2.04, 2.84 mg/kg in the wet and dry seasons, respectively. However, the degradation rale in both seasons followed first-order kinetics. Half-lives in green shoots were in range 1.43-1.70 and 2.10-2.21 days and in made tea 1.59-1.73 and 1.87-1.94 days for wet and dry seasons, respectively. During processing of green shoots to made tea considerable loss (42-70%) of residue was observed. The transfer of residue from made tea brew was in the range 3-22%. In brew residue were below 0.02 mg/l after 5 days of application at both the rates in either of the seasons. The estimated intake with brew (normal consumption of 10 cup/day/adult) thus would be below the acceptable daily intake for fenazaquin (0.005 mg/kg-body weight). To avoid health hazards due to the toxic effect of residues in brew, a waiting period for plucking the tea shoots after fenazaquin application of more than 5 days for both the seasons at recommended rate (125 g AI/ha) may be suggested and considered quite safe.     

Changes in Escherichia coli resistance to co-trimoxazole in tuberculosis patients and in relation to co-trimoxazole prophylaxis in Thyolo,Malawi

In Thyolo district, Malawi, an operational research study is being conducted on the efficacy and feasibility of co-trimoxazole prophylaxis in preventing deaths in HIV-positive patients with tuberculosis (TB). A series of cross-sectional studies were carried out to determine i) whether faecal Escherichia coli (E.coli) resistance to co-trimoxazole in TB patients changed with time and ii) whether the resistance pattern was different in HIV positive TB patients who were taking co-trimoxazole prophylaxis. Co-trimoxazole resistance among E.coli isolates in TB patients at the time of registration was 60% in 1999 and 77% in 2001 (p<0.01). Resistance was 89% among HIV-infected TB patients (receiving co-trimoxazole), while in HIV negative patients (receiving anti-TB therapy alone) it was 62% (p<0.001). The study shows a significant increase of E.coli resistance to co-trimoxazole in TB patients which is particularly prominent in HIV infected patients on co-trimoxazole prophylaxis. Since a high degree of plasmid-mediated transfer of resistance exists between E.coli and the Salmonella species, these findings could herald limitations on the short and long term benefits to be anticipated from the use of co-trimoxazole prophylaxis in preventing non-typhoidal salmonella bacteraemia and enteritis in HIV infected TB patients in Malawi.     

Acute and short-term toxicity studies on p-aminodiphenylamine

p- Aminodiphenylamine (p-ADPA), an aromatic amine of wide industrial applications, also finds human exposure through hair dye preparations or via ingestion of a common food colouring metanil yellow. Acute and short-term toxicity studies in albino rats have been done following the biochemical markers, hematology and tissue histopathology. The acute LD50 value of p-ADPA is 0.847 g/kg body weight which qualifies for the 'moderately toxic' category. In short-term studies, animals were fed p-ADPA, mixed in routine laboratory diet at the concentrations of 0.0 (control), 0.1, 0.25, 0.5 and 0.75% (w/w), daily for 90 days. Feed intake and body weight gain in the highest dosed group were reduced. Hematological examinations exhibited moderate anemic conditions with decreased red blood cells, increased erythrocyte sedimentation rate and lowered packed cell volume suggesting normocytic normochromic anemia at 0.25% onward levels of p-ADPA intake. There was significant increase in the activities of acid/alkaline phosphatases and GOT/GPT in serum with simultaneous depletion from liver at the levels of 0.5 and 0.75% p-ADPA intake, suggesting biochemical lesions of the liver. Testicular LDH and hyaluronidase were lowered at 0.5 and 0.75% levels indicating partial arrest of spermatogenesis. These findings were supported histopathologically. The study warrants careful consideration on its exposure, industrially or through common food color or hair dye preparations.     

Papillon-Lefevre Syndrome

Papillon-Lefevre syndrome in six Saudi children in the same family is described. The parents were unaffected, and parental consanguinity was present. Palmoplantar keratosis started at the age of 1 1/2 years. The loss of deciduous teeth was a consequence of juvenile periodontitis. All essential features of the syndrome were present in this series.     

Demographic characteristics and prevalence of serologic markers among donors who use the confidential unit exclusion process: the Retrovirus Epidemiology Donor Study

BACKGROUND: Most blood centers utilize a confidential unit exclusion (CUE) process, intended to reduce the risk of transfusion-associated infectious diseases by allowing high-risk donors confidentially to exclude their blood from use for transfusion. The effectiveness of this method remains controversial. STUDY DESIGN AND METHODS: Confirmatory or supplemental test results for antibodies to human immunodeficiency virus, human T-lymphotropic virus type I, and hepatitis C virus, as well as hepatitis B surface antigen and syphilis and screening test results for antibodies to hepatitis B core (antigen) and alanine aminotransferase levels were obtained for approximately 1.8 million units donated during 1991 and 1992 at five blood centers within the United States. The prevalences of these infectious disease markers in units that the donors confidentially excluded (CUE+) and units that the donors did not exclude (CUE-) were calculated and examined within demographic subgroups. RESULTS: Units that were CUE+ were 8 to 41 times more likely to be seropositive for antibodies to human immunodeficiency virus and hepatitis C virus, hepatitis B surface antigen, and syphilis and three to four times more likely to react for antibody to hepatitis B core (antigen) or to have elevated alanine aminotransferase levels than units that were CUE- (p < 0.001). The positive predictive value of CUE (the percentage of CUE+ units that were confirmed seropositive for any marker) was 3.5 percent, and the sensitivity of CUE (the percentage of confirmed-seropositive units that were CUE+) was 2.3 percent. CONCLUSION: The current CUE process has low sensitivity and apparently low positive predictive value, and in many cases, it appeared that donors misunderstood it. Yet, CUE was not a “random process,” as CUE+ units were more likely to be seropositive for any infectious disease marker than CUE- units. This suggests that efforts to improve the CUE system may be warranted. As risk factors for transfusion-transmitted infection become more difficult to identify by history-based screening, however, such efforts may have limited effect.