Improvements on a patient-specific dose estimation system in nuclear medicine examination.

The purpose of this paper is to develop a patient-specific dose estimation system in nuclear medicine examination. A dose deposition routine to store the deposited energy of the photons during their flights was embedded in the widely used SimSET Monte Carlo code and a user-friendly interface for reading PET and CT images was developed. Dose calculated on ORNL phantom was used to validate the accuracy of this system. The ratios of S value for (99m)Tc, (18)F and (131)I computed by this system to those obtained with OLINDA for various organs were ranged from 0.93 to 1.18, which were comparable to that obtained from MCNPX2.6 code (0.88-1.22). Our system developed provides opportunity for tumor dose estimation which cannot be known from the MIRD. The radiation dose can provide useful information in the amount of radioisotopes to be administered in radioimmunotherapy.

[Effect of daphnetin on the exo-erythrocytic stage of rodent malaria].

OBJECTIVE: To investigate the activity of daphnetin(DPNT) against the exo-erythrocytic stage of rodent malaria. METHODS: Groups of ten male ICR mice were infected by intraperitoneal injection with sporozoites of P. yoelii. Mice were administered daphnetin 0.5 hr postinfection on d0 and once per day for three additional consecutive days(d1-d3) by the i.g. route. The effects of daphnetin at various dosages and those of the combination of daphnetin with primaquine were assessed by the number of mice with negative Giemsa-stained slides from tail blood on the seventh day after infection and by the average number of red blood cells (RBC) infected in 1,000 RBC observed on the eleventh or twelfth day after infection. We also observed the effect of daphnetin on the concentration of Hb in ICR mice. RESULTS: Daphnetin exhibited no detectable antimalarial effect on the exo-erythrocytic stage of P. yoelii, while the antimalarial efficacy of DPNT 50 mg/(kg.d) combined with 5 mg/(kg.d) PQ, was comparable to PQ 10 mg/(kg.d) x 4 d i.g. in mice infected with sporozoites of P. yoelii. The concentration of Hb in ICR mice administered with DPNT 50 mg/(kg.d) x 4 d decreased on the eighth day after administration. CONCLUSION: Daphnetin alone showed no anti-exoerythrocytic activity in vivo. The combination of DPNT 50 mg/(kg.d) with PQ 5 mg/(kg.d) showed promising antimalarial efficacy comparable to that of PQ 10 mg/(kg.d). Administration of DPNT caused anemia in ICR mice.

[Studies on pharmacokinetics of chloroquine in mice infected with chloroquine-resistant strain of Plasmodium berghei].

OBJECTIVE: To compare the pharmacokinetic differences of chloroquine in normal mice and the mice infected with the N and the RC strains of Plasmodium berghei. METHODS: The concentrations of chloroquine in the plasma of normal mice and the mice infected with the N or the RC strains of P. berghei were analyzed by reverse-phase HPLC. The pharmacokinetic parameters were measured with software 3P87. RESULTS: The t1/2 beta value was significantly lower in the mice infected with the RC strain than in normal mice and the mice infected with the N strain(P < 0.05), however, there were no significant differences between the mice infected with the N strain and normal mice. CONCLUSION: Elimination of chloroquine in the mice infected with the RC strain of P. berghei speed up significantly comparing with the mice infected with the N strain.

The schizontocidal activity of daphnetin against malaria parasites in vitro and in vivo.

OBJECTIVE: To investigate the in vitro and in vivo schizontocidal activity of daphnetin. METHODS: Schizontocidal activity of daphnetin was tested using an in vitro assay based on the routine in vitro cultivation of P. falciparum FCC1 strain. The in vivo antimalarial effects of daphnetin at various dosages were assessed in mice infected with P. b. erghei ANKA according to "4-day suppress assay". RESULTS: In vitro, daphnetin exhibited potent schizontocidal activity comparable to chloroquine(CQ) at the dose range of 1-10 mumol/L. In vivo, 50 or 100 mg/kg.d-1 x 4 d daphnetin i.g. and 10, 50 or 100 mg/kg.d-1 x 4 d dephnetin i.p. showed antimalarial efficacy comparable to CQ 10 mg/kg.d-1 x 4 d i.g. in mice infected with P. berghei ANKA, evaluated by both the reduction rate of parasitemia on D4 and the average surviving days in 30 days. CONCLUSION: Daphnetin displays certain schizontocidal activity both in vitro and in vivo.

Mouse liver microsomal metabolism of chloral hydrate, trichloroacetic acid, and trichloroethanol leading to induction of lipid peroxidation via a free radical mechanism.

Metabolism of chloral hydrate (CH) by male B6C3F1 mouse liver microsomes (control-microsomes) generated free radical intermediates that resulted in endogenous lipid peroxidation, forming malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT), acetone, and propionaldehyde. Because MDA, FA, and ACT are tumorigens, endogenous formation of lipid peroxidation products via a free radical mechanism may be responsible for hepatocellular tumorigenicity of CH to the B6C3F1 mice. Trichloroacetic acid (TCA) and trichloroethanol (TCE), the primary metabolites of CH, also generated free radicals and induced lipid peroxidation. Lipid peroxidation from TCA equaled that induced by CH, whereas that from TCE was 3- to 4-fold lower, suggesting that metabolism of CH to TCA may be the predominant pathway leading to lipid peroxidation. Metabolism of CH, TCA, and TCE by liver microsomes of mice pretreated with pyrazole (pyrazole-microsomes) yielded lipid peroxidation products at a level 2- to 3-fold higher than those from liver microsomes of untreated mice. In addition, CH-induced lipid peroxidation catalyzed by control-microsomes and pyrazole-microsomes was reduced significantly by 2,4-dichloro-6-phenylphenoxyethylamine, a general cytochrome P450 inhibitor. Thus, our study suggests that cytochrome P450 is the enzyme catalyzing the metabolic activation of CH and its metabolites (TCA and TCE) leading to lipid peroxidation, and that CYP2E1 may be the major isozyme responsible. This latter conclusion was supported by results using human lymphoblastoid cells expressing cytochrome P4502E1, which metabolized CH to reactants inducing mutations, whereas the parental cell line was inactive.

Formation of malondialdehyde-modified 2'-deoxyguanosinyl adduct from metabolism of chloral hydrate by mouse liver microsomes.

We previously reported that metabolism of chloral hydrate (CH), a widely used sedative and hypnotic, by male B6C3F1 mouse liver microsomes resulted in lipid peroxidation, producing the tumorigen malondialdehyde (MDA). Now we have found that incubation of CH in the presence of calf thymus DNA resulted in the formation of an MDA-modified DNA adduct as detected by 32P-postlabeling analysis. Similar results were obtained from incubation of trichloroacetic acid and trichloroethanol, both metabolites of CH.

Hepatic metabolism of chloral hydrate to free radical(s) and induction of lipid peroxidation.

Metabolism of chloral hydrate by male B6C3F1 mouse liver microsomes generates free radical intermediate(s) as evidenced by electron spin resonance spectroscopic analysis. The subsequent induction of endogenous lipid peroxidation was shown by analysis of the resulting products with high-pressure liquid chromatography. Chloral hydrate was found mutagenic in Salmonella typhimurium strain TA104. Both lipid peroxidation and mutagenicity were efficiently inhibited by free radical scavengers, alpha-tocopherol and menadione.

Rat liver microsomal and mitochondrial metabolism of primaquine in vitro.

The profiles of major metabolites of primaquine (PQ) produced from liver microsomal (MC) and mitochondrial (MT) metabolism were investigated in vitro by silica gel thin layer and reverse phase high pressure liquid chromatography (HPLC). The results indicated that 5-hydroxy primaquine (5-OH PQ) and carboxyprimaquine (CPQ) were simultaneously produced by either microsomes or pure mitochondria preparations. However, the quantitative study showed that microsomes produced approximately 19 times more 5-OH PQ but only 1/34 of the CPQ by mitochondria.

[In vitro liver microsomal metabolism of antimalarial primaquine].

The profile of the major metabolites of primaquine produced by in vitro liver microsomal metabolism was investigated with silica gel thin-layer and high performance liquid chromatography (HPLC) analysis. The results indicated that the liver microsomal metabolism could simultaneously produce both 5-OH PQ (quinoline ring oxidation product) and CPQ (side-chain oxidative deamination product). However, the quantitative comparative study of microsomal metabolism showed that the production of 5-OH PQ was far much higher than that of CPQ.

Comparative regioselective and stereoselective metabolism of 7-chlorobenz[a]anthracene and 7-bromobenz[a]anthracene by mouse and rat liver microsomes.

Quantitative metabolism of 7-chlorobenz[a]anthracene (7-Cl-BA) and 7-bromobenz[a]anthracene (7-Br-BA) by liver microsomes of uninduced mice and rats was studied. Both enzymatic systems metabolize 7-Cl-BA preferentially at the C-8 and C-9 aromatic double bond region, approximately 42 and approximately 56% respectively, of the total metabolites. 7-Cl-BA and 7-Br-BA were metabolized considerably at C-3 and C-4, C-5 and C-6, C-8 and C-9, and C-10 and C-11. While 7-Cl-BA trans-3,4-dihydrodiol was formed in a 7-8% yield of the total metabolites in both enzymatic systems, 7-Br-BA trans-3,4-dihydrodiol was formed 16.0 and 9.9% respectively, from the mouse and rat liver microsomal metabolism. In mutagenicity assays with the Salmonella typhimurium tester strain TA100 in the presence of S9 activation enzymes, both of these trans-3,4-dihydrodiols exhibited higher mutagenicity than 7-Cl-BA and 7-Br-BA, while the other trans-dihydrodiol metabolites were either essentially inactive or weaker than the parent compounds. These results suggest that 7-Cl-BA trans-3,4-dihydrodiol and 7-Br-BA trans-3,4-dihydrodiol are the proximate metabolites of 7-Cl-BA and 7-Br-BA. Metabolism of 7-Cl-BA and 7-Br-BA by mouse liver microsomes was also in a stereoselective manner, preferentially giving trans-dihydrodiol metabolites an R, R stereochemistry.

[Study on structure-activity relationships of hemolytic toxicity of primaquine derivatives].

Primaquine (PQ) and it's 13 derivatives were tested in an in vitro assay system incorporated with liver-microsomal metabolism for their hemolytic toxicity, and 6 putative metabolites of PQ were also assayed in the same system without microsomal metabolism. The results showed that in the 13 derivatives, the hemolytic toxicity of 4-methyl PQ derivatives was lower than that of PQ while 5-trifluoroacetyl PQ derivatives exhibited similar hemolytic potential to PQ. Various modification of the 8-amino side chain of PQ has no significant effect on the hemolytic toxicity of PQ. In the 6 putative metabolites of PQ, 5-OH PQ and 5,6-OH PQ were the most potent hemolytic toxidants which could produce similar level of methemoglobin formation at concentrations several orders of magnitude less than that of PQ, while the hemolytic toxicity of 6-OH PQ, AQD and AQL was also higher than that of PQ itself. MAQ was the only one which exhibited no hemolytic toxicity.

[In vitro assay for detecting hemolytic toxicity of antimalarials incorporated with microsomal metabolic system].

The in vitro metabolic system comprised NADP co-factors and liver microsomes isolated from male rats pre-treated with phenobarbital, 60 mg/kg, i.p. for 3d combined with a single i.p. dose of 80 mg/kg of naphtholflavone. The 1% RBC suspension was made up from G6PD-deficient rabbit blood. Primaquine, chloroquine and M 8506 at various dosages were incubated at 37 degrees C with the microsomal metabolic system in vitro respectively. The supernatants were incubated with 1% RBC suspension. The OD635nm values of the supernatants were detected after incubation and centrifugation. The results showed that both primaquine and M 8506 exhibited potent hemolytic toxicity at the dose-range of 1.5-3 x (10(1)-10(3) mumol/L, with certain dose-effect relationship, while chloroquine exhibited no hemolytic toxicity. It is suggested that the in vitro assay incorporated with microsomal metabolic system might be a useful preliminary screening method for testing hemolytic toxicity of various antimalarials.

Mutagenicity of nitrofurans in Salmonella typhimurium TA98, TA98NR and TA98/1,8-DNP6.

8 representative 2-substituted 5-nitrofurans were assayed for mutagenicity in Salmonella typhimurium strains TA98, TA98NR and TA98/1,8-DNP6. The tested compounds were: 5-nitro-2-furanacrylic N-(5-nitro-2-furfurylidene)hydrazide (1); furazolidone (2); 5-nitro-2-furanacrolein (3); 5-nitro-2-furaldehyde semicarbazone (4); 5-nitro-2-furaldehyde (5); nitrofurantoin (6); 5-nitro-2-furaldehyde diacetate (7); and 5-nitro-2-furoic acid (8). These compounds exhibited markedly different mutagenic activities in TA98, and these mutagenicities were similar both in the presence and the absence of rat-liver hepatic S9 activation enzymes. The mutagenic responses ranged from potent (90-300 revertants/nmole, compounds 1-3), to medium (about 10 revertants/nmole, compounds 4 and 6), to weak (0-4 revertants/nmole, compounds 5, 7 and 8). The mutagenicity of 3 was similar in all 3 tester strains, while compound 8 was essentially inactive. The mutagenicities of 1, 4, 5 and 7 were decreased 30-75% in TA98NR, while 2 and 6 showed an even greater depression of activity in this strain. Compound 6 with S9 was about equally mutagenic in TA98 and TA98/1,8-DNP6, while the activities of 6 without S9 and 2 and 7 both with and without S9 were 50-75% lower in TA98/1,8-DNP6. Compounds 1, 4 and 5 were only about 5-10% as mutagenic in TA98/1,8-DNP6 as in TA98. These results suggest that: (i) nitrofurans and their S9-mediated metabolites have similar mutagenic potencies; (ii) with the possible exception of No. 3, nitroreduction is the major route of mutagenic activation for these nitrofurans; and (iii) for compounds 2, 6 and 7, both the presumed N-hydroxy and N,O-ester derivatives of the corresponding aminofuran metabolites appear to lead to mutations.