We evaluated the in vivo biodistribution of indium- and yttrium-labeled second-generation polyamidoamine dendrimer (PAMAM) conjugated with 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M), a derivative of DTPA. In addition, we conjugated PAMAM-1B4M to humanized anti-Tac IgG (HuTac) and evaluated its in vitro and in vivo properties. PAMAM-1B4M was labeled with 111In at 37-48 MBq/mg (1.0-1.3 mCi/mg) or with 88Y at 3.7-4.8 MBq/mg (0.1-0. 13 mCi/mg), and an aliquot of radiolabeled conjugate was saturated with the corresponding stable yttrium or indium. Nontumor-bearing nude mice were injected intravenously with 55.5-66.6 kBq (1.5-1.8 microCi) of 88Y-labeled PAMAM-1B4M or with 185 kBq (5 microCi) of 111In-labeled PAMAM-1B4M. The mice were then sacrificed at 15 min, 90 min, 1 day, and 4 days postinjection. Then the PAMAM-1B4M was conjugated with HuTac and labeled with 111In at 111-259 MBq/mg (3-7 mCi/mg). Another preparation of 111In-labeled HuTac-PAMAM-1B4M was saturated with stable indium. Immunoreactivity of both preparations and biodistribution in normal mice 1 h after injection and in ATAC4 and A431 tumor-bearing mice 18 h after injection were evaluated and compared with those of 111In-labeled 1B4M-HuTac. We noted significantly higher accumulations (p < 0.05) of 111In-labeled and 88Y-labeled unsaturated PAMAM-1B4M than saturated preparations in the liver, kidney, spleen, and bone at most time points. The whole-body clearance times of unsaturated preparations were significantly slower than those of saturated preparations at all time points, with the exception of 168 h for 111In-labeled PAMAM-1B4M. The saturated preparation of 111In-labeled HuTac-PAMAM-1B4M showed lower hepatic uptake (27 +/- 2%ID/g) than the unsaturated (32 +/- 2%ID/g), but greater than the HuTac-1B4M control (10 +/- 0%ID/g). The splenic uptake showed 15 +/- 1, 38 +/- 5, and 8 +/- 1%ID/g for the saturated, unsaturated, and control, respectively. The biodistribution of the dendrimer conjugated HuTac in normal organs of tumor-bearing mice was similar to nontumor-bearing mice. Specific tumor (ATAC4) uptake was higher than that in nonspecific tumor (A431). In conclusion, we evaluated the biodistribution of radiolabeled PAMAM-1B4M. We noted high accumulation in the liver, kidney, and spleen, which significantly decreased when the chelates were saturated with the stable element. A similar phenomenon was observed between unsaturated and saturated 111In-labeled HuTac-PAMAM-1B4M, indicating that the PAMAM dendrimer had a detrimental effect on biodistribution.

Animals↗

PubMedDate not supplied

Chemical modification to reduce renal uptake of disulfide-bonded variable region fragment of anti-Tac monoclonal antibody labeled with 99mTc.

The anti-Tac disulfide-bonded variable region fragment (dsFv) is a genetically engineered, 25 kDa, murine monoclonal antibody fragment that recognizes the alpha subunit of the interleukin-2 receptor (IL-2Ralpha). The dsFv radiolabeled with the tetrafluorophenyl ester (TFP) of [99mTc]mercaptoacetyltriglycine ([99mTc]MAG3-TFP) showed rapid tumor uptake and fast blood clearance in mice, resulting in high tumor-to-nontumor background ratios. However, its high renal uptake was a problem. In this study, we tested the effect of lowering the isoelectric point (pI) of dsFv to <9.3 on renal and tumor uptake. To lower the pI, dsFv was acylated simultaneously with both [99mTc]MAG3-TFP and TFP-glycolate. The acylation of dsFv decreased its pI and its immunoreactivity inversely proportional to the molar ratio of TFP-glycolate to dsFv, whereas the conjugation of [99mTc]MAG3-TFP alone did not. When biodistribution studies were performed in nude mice, the effect of the lowered pI was reflected primarily in decreased kidney uptake and whole-body retention, with its highest effect seen at the earliest time point (15 min) after injection. In tumor-bearing nude mice, glycolated [99mTc]MAG3-dsFv with a pI range of 4.9 to 6.5 accumulated selectively into IL-2 receptor-positive SP2/Tac tumor similar to that of the control [125I]dsFv labeled by the Iodo-Gen method, whereas its renal uptake was 25% of [125I]dsFv at 15 min. At 90 min, the ratios of tumor to receptor-negative SP2/0 tumor, liver, kidney, stomach, and blood had peaked at 10.9, 8.5, 0.3, 5.0, and 6.2, respectively, for the glycolated [99mTc]MAG3-dsFv. The corresponding ratios for [125I]dsFv were 3.7, 5.0, 0.1, 1.5, and 2.1, respectively.

Animals↗

PubMedDate not supplied

Determination of nalbuphine in drug abusers' urine.

Nalbuphine, chemically derived from the oxymorphone, is a potent analgesic with narcotic antagonist activity. Because of the limited availability of methamphetamine, the abuse of nalbuphine as an alternative for methamphetamine began in late 1991 in Korea. In this study, the analysis of nalbuphine by gas chromatography (GC) was investigated. Using solid-phase extraction, we analyzed drug abusers' urine samples in order to quantitate nalbuphine by GC after trimethylsilyl derivatization with N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA), trimethylsilylimidazole (TSIM), and 1% trimethylchlorosilane (TMCS) (100:2:5). Nalbuphine and its two metabolites, nornalbuphine and 6-ketonalbuphine, were identified by gas chromatography-mass spectrometry. The ratio of total (i.e., nonconjugated and glucuronide) nalbuphine to nonconjugated nalbuphine ranged from 1.8 to 3.0 in the five drug abusers' urine. The urinary excretion of nalbuphine showed that 93% of nalbuphine was excreted in 6 h after intraperitoneal administration of 10 mg/kg nalbuphine to five rats. No nalbuphine was detected in the urine specimens of rats from 24 to 48 h.

Animals↗

PubMedDate not supplied

Fine needle aspiration cytology of primary pulmonary paraganglioma. A case report.

BACKGROUND: Primary pulmonary paragangliomas are rare tumors. To our knowledge, there is no prior report on fine needle aspiration cytology (FNAC) in pulmonary paraganglioma. CASE: A 34-year-old man presented with an incidentally found solitary pulmonary mass. FNAC showed papillarylike clusters of epithelioid cells with round to oval nuclei, evenly dispersed chromatin, micronucleoli and occasional anisonucleosis. These cytologic features were suggestive of a sclerosing hemangioma or bronchioloalveolar carcinoma. A right lower lobectomy revealed a primary pulmonary paraganglioma. CONCLUSION: The possibility of pulmonary paraganglioma should be considered in the differential diagnosis of FNAC showing pseudopapillary clusters of epithelioid cells.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMedDate not supplied

Fine needle aspiration cytology of cystic hypersecretory carcinoma of the breast. A case report.

BACKGROUND: Cystic hypersecretory carcinoma (CHC) of the breast is a rare variant of intraductal carcinoma. It is characterized by a multicystic, yellow-brown lesion with gelatinous material grossly and cystically dilated ducts with an eosinophilic secretion microscopically. The histologic or cytologic features can be deceptively bland. CASE: A 37-year-old female presented with an 8-cm-diameter, firm mass in the breast. Radical mastectomy was performed after fine needle aspiration (FNA). The moderately cellular smear had a characteristic background of proficient, intensely staining secretion with bubbling. The cellular components were various, ranging from sheets of benign hyperplastic ductal cells to three-dimensional clusters or papillae of frankly malignant ductal cells, with varying degrees of secretory activity. The background consisted of inflammatory cells, naked nuclei and foamy histiocytes. The cytologic findings correlated well with the histologic features of the tumor, which showed both micropapillary intraductal carcinoma with apocrine metaplasia and focal high grade invasive carcinoma in a background of cystic hypersecretory hyperplasia. CONCLUSION: This was the first reported case of FNA cytology of an invasive form of CHC. CHC has characteristic features on FNA, and so a reliable diagnosis can be made.

Adult↗

PubMedDate not supplied

Studies on hypoxia: XI. Long-term effects on the epiphyseal plate--a histomeric and radioautographic study.

Rats were exposed to hypoxia for one week. The mean thickness of epiphyseal plates form control rats was 430 micrometers (mum) which was reduced to 313 mum in hypoxic rats. Radioautographic incorporation of 3H-phenylalaine by connective tissue cells in hypoxic rats was reduced up to 38% in control rats.

Animals↗

PubMedDate not supplied

Studies on hypoxia: XII. Detrimental effects of synthetic polyribonucleotides on epiphyseal plates of rats exposed to hypoxia.

The effect of different doses of polyadenylic and polyuridylic acids (poly A:U) was studied in control rats and in rats exposed to hypoxia. In the control rats, administration of different doses of poly A:U did not change the thickness of the epiphyseal plate or increase the incorporation of 3H-phenylalanine as judged using radioautography. Rats exposed to hypoxia showed a significant dose-related reduction in the thickness of the epiphyseal plate and 3H-phenylalanine incorporation.

Amino Acids↗

PubMedDate not supplied

Delivery of hydrocortisone from liposomal suspensions to the hairless mouse skin following topical application under non-occlusive and occlusive conditions.

The in-vivo cutaneous absorption of hydrocortisone was examined following topical application of hydrocortisone-containing liposomes. The formulation was applied onto the skin (1.0 cm2) of the hairless mouse (at a dose of 0.1 mg hydrocortisone) in the presence and absence of occlusion, and temporal profiles of the drug in the skin (stratum corneum and viable skin) were monitored. Under the non-occluded condition, the drug amount in the stratum corneum and viable skin reached its maximum within 1 h, and then decreased rapidly. Gelation of the liposomes by complete dehydration of the formulation under non-occlusion, which may prevent partition of the drug into the skin, appears to be a cause of the rapid decrease. Under the occluded condition, the drug amount in the skin was sustained although it then decreased dramatically compared with that under the non-occlusion (i.e. approximately 1/22 for stratum corneum and 1/8 for viable skin at 1 h, for example). A prevention of gelation of the liposomes by occlusion appears to be a potential mechanism of the maintenance of the drug concentration in the skin. The dramatic decrease in drug content in the skin may be attributed to the reduced partition of hydrocortisone, a hydrophobic drug, from the liposomes into the hydration-maintained stratum corneum under occlusion. In both application conditions, the concentration of hydrocortisone in the hydrophilic viable skin layer was markedly lower than that in the stratum corneum, indicating that partitioning between these tissues is a primary determinant of hydrocortisone reaching viable skin tissue. The estimated penetration depth of the drug into the stratum corneum was not affected significantly by the application conditions. These results demonstrate that excessive dehydration (non-occlusion) is not desirable for the prolonged delivery of hydrocortisone from liposomes into the skin. They also indicate that either hydration of the dosed skin (occlusion) is not preferable for the efficient delivery of hydrocortisone from the liposomes to the skin, especially to the viable skin. Therefore, both excessive dehydration of the liposomes and excessive hydration of the dosed skin (occlusion) should be avoided in the topical application of liposomal formulations for efficient delivery of hydrocortisone to the skin for a prolonged period of time.

Administration, Oral↗

PubMedDate not supplied

Analysis of correlation between rectal complications and rectal dose following high dose rate intracavitary radiotherapy in patients with uterine cervix cancer: in vivo dosimetric analysis.

PURPOSE: To investigate the correlation between late rectal complications and rectal dose in uterine cervix cancer patients treated with high dose rate intracavitary radiotherapy (HDR ICR) and to analyze dose factors reducing complications. METHODS: A retrospective analysis was done of 74 patients treated with external beam RT and HDR ICR between 1995 and 1997. Radiotherapy (RT) consisted of a median 50.4 Gy external beam plus six fractions of HDR ICR given two times per week, concurrent with the last three weeks of external beam therapy, to a total dose of median 24 Gy to point A or the reference point. Rectal doses were calculated at rectal reference points using barium contrast criteria. In vivo measurement of rectal dose was performed with thermoluminescent dosimeters (TLD) immediately prior to the first fraction of HDR ICR. RESULTS: Eight patients developed rectal complications (11%). There was a significant difference between measured rectal doses for patients with rectal complications and those without (p < 0.05), and the doses were higher in complicated patients. A significant increase in the probability of development of complications was found for patients receiving measured rectal doses of ICR fractional dose 320 cGy or more, ICR total dose 2000 cGy or more, and ICR% to point A 80% or more. CONCLUSIONS: This study showed that in vivo dosimetry using TLD during HDR ICR could have a useful role as a predictor of late rectal complications. Dose limitation to the rectum could possibly be achieved by thorough vaginal packing or use of an applicator with proper shielding while maintaining a high dose to the tumor.

Adult↗