Biomedical subjects

R Siegler

Publications and source records attributed to R Siegler.

At least 19 recordsLinked to original sources

PubMed1992

Renal prostacyclin biosynthesis is reduced in children with hemolytic-uremic syndrome in the context of systemic platelet activation.

Previous studies have reported various abnormalities in prostacyclin (PGI2) synthesis and metabolism in hemolytic-uremic syndrome (HUS). However, the conclusions of most of these studies are based on in vitro or ex vivo experiments that only give an indirect estimate of the actual biosynthesis in vivo. We studied the urinary excretion of PGI2 metabolites, taken as a marker of the actual biosynthesis, in six children with HUS during the acute phase of the disease and again when remission was achieved. Eight age- and sex-matched healthy children were studied as controls. Since HUS is also associated with platelet activation and consumption, we also studied the urinary excretion of thromboxane A2 (TxA2) metabolites. Urinary PGI2 and TxA2 metabolites were assessed by radioimmunoassay after high-performance liquid chromatography (HPLC) purification. Urinary excretion of the PGI2 hydrolysis product, 6-keto-PGF1 alpha, was significantly reduced in children with acute HUS as compared with controls, indicating a defective renal synthesis of PGI2. A significant inverse correlation was found between urinary 6-keto-PGF1 alpha and blood urea nitrogen (BUN), as well as plasma creatinine. At remission, urinary 6-keto-PGF1 alpha levels increased to values higher than those of controls. By contrast, the urinary excretion of the major PGI2 beta-oxidation product, 2,3-dinor-6-keto-PGF1 alpha, was comparable to controls, indicating normal systemic PGI2 biosynthesis. The urinary excretion of both TxA2 hydrolysis product, TxB2, and the major beta-oxidation metabolite, 2,3-dinor-TxB2, were lower than normal in the acute phase of HUS if expressed as absolute values.(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗

PubMed1989

Suitability of DTAF as a fluorescent labelling reagent for direct analysis of primary and secondary amines--spectral and chemical reactivity considerations.

DTAF has been used successfully to prepare fluorescent labelled reagents for fluorescence polarization immunoassays. Its applicability as a derivation reagent for direct fluorescence analysis of primary and secondary amines was evaluated. DTAF was shown to have spectral properties that closely resemble those of fluorescein and that are apparently insensitive to the presence of the triazine nucleus. Spectrally determined pKa values also closely resemble those of fluorescein and other amino aryl-s-triazines. DTAF is prone to hydrolytic degradation with the rate of reaction increasing with increasing pH, until a pH value is reached at which ionization of the amine bridging the two aromatic nuclei occurs; at this pH the rate reaches a plateau value. Both primary and secondary amines react efficiently with DTAF, and the reactivity increases with the increasing basicity of the amine reactants. The reaction is pH-dependent, proceeding most efficiently at pH values at which both the "bridging amine" of DTAF and the amine substrate are unionized. Methyl substituted secondary amines were consistently more reactive than the corresponding primary amine, but further imposition of steric bulk about the amine nitrogen significantly reduced the reactivity of amines toward DTAF. In cases where such steric bulk is minimal. DTAF appears to be a suitable fluorescent labelling reagent for direct analytical applications.

Amines↗

PubMed1989

In vivo assessment of 111In-labeled hematoporphyrin derivative in breast tumor-bearing animals.

The biological behavior of 111In-labeled HPD has been investigated in tumor-bearing animals. Mice mammary adenocarcinomas and 7,12-dimethylbenz(a)anthracine induced breast tumors in Sprague-Dawley female rats were clearly visualized by 111In-HPD nuclear scintigraphy. Optimal scans were obtained after a 48 h delay. In normal and tumor-bearing animals, the highest uptake of 111In-HPD 72 h post-injection was found in the liver, the spleen and the kidneys. Depending on the size and the extent of necrosis, the uptake of 111In-HPD by malignant breast tumors varied from 2.5% injected dose (ID) (range 0.14-5.3% ID) in mice to 1% (range 0.22-8.1% ID) in rats. Benign breast tumor uptake of 111In-HPD was less than 1% ID. No significant amount of the radiopharmaceutical was found in pulmonary abscesses and abdominal cysts (less than 0.1% ID). Scintigrams of these infectious or inflammatory lesions were normal. Malignant tumor to blood, heart and lung ratios averaged 50:1, 10:1 and 3:1 respectively. Tumor to brain ratio ranged from 72 to 444:1.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1989

Scintigraphic detection of atherosclerotic plaques in rabbits with 111In-labeled hematoporphyrin derivative.

The efficacy of 111In-labeled hematoporphyrin derivative (HPD) in localizing and detecting atheromas had been investigated with 10 atherogenic New Zealand white rabbits. Atherosclerotic plaques surgically induced in the abdominal aorta showed selective uptake of 111In-HPD over normal blood vessels averaging 0.01% ID/g tissue (range 0.003-0.023% ID/g). Normal aorta and thoracic artery concentrated an average of 0.0026% ID/g which is less than the mean blood activity of 0.0034% ID/mL. Statistical analysis demonstrated significant difference in the uptake of 111In-HPD by the atherosclerotic plaque segments as compared to normal abdominal aorta (P = 0.0023) and normal thoracic artery (P = 0.0012). In hypercholesteremic rabbits, the mean plaque segment to normal blood vessels ratio was 4:1 (range 2 to 9:1) sufficiently high to permit plaque delineation in the scintigram. Although 111In-HPD showed promise as a plaque imaging agent, further investigation with large animal models such as primates is needed to confirm current findings.

Animals↗

PubMed1985

Phase I evaluation and pharmacokinetics of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193).

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, TCAR, Riboxamide, NSC 286193) is a novel C-nucleoside with antitumor activity against several murine tumor models, including Lewis lung carcinoma. The mechanism whereby this compound exerts its antineoplastic effects is most likely related to a state of guanine nucleotide depletion whereby the anabolite, thiazole-4-carboxamide adenine dinucleotide, potently inhibits inosine-5'-monophosphate dehydrogenase. This Phase I study was designed to determine the maximally tolerated dose of Tiazofurin administered on a 5-day, every-28-day schedule. Tiazofurin levels were measured using a high-pressure liquid chromatography assay, and pharmacokinetic studies were performed in patients treated at each dose level. Nineteen patients received a total of 24 courses of the drug in doses ranging from 550 to 2200 mg/sq m. The dose-limiting toxicities were pleuropericarditis and a general illness best described as a "viral-like" syndrome (manifested by severe malaise, headaches, myalgias, fever, nausea, vomiting, and diarrhea). Other toxicity included myelosuppression, hyperuricemia, elevated serum creatine phosphokinase and serum glutamic oxaloacetic transaminase, conjunctivitis, mucositis, and desquamation of the palms of the hands. Plasma clearance of Tiazofurin followed a biexponential pattern with a harmonic mean terminal half-life of 7.6 h. The mean volume of distribution at steady state was 30 liters/sq m, and the mean plasma clearance was 3 liters/h/sq m. The total cumulative urinary excretion ranged from 15 to 49%. The maximally tolerated dose of Tiazofurin on a 5-day schedule was 1650 mg/sq m. The recommended dose for Phase II evaluations is 1100 mg/sq m for 5 days. However, exploration of other schedules which might allow administration of more Tiazofurin combined with biochemical studies including thiazole-4-carboxamide adenine dinucleotide measurements would be desirable.

Adult↗

PubMed1983

In vivo assessment of 99mTc-labeled hematoporphyrin derivative in tumor-bearing animals.

The efficacy of 99mTc-labeled hematoporphyrin derivative in localizing neoplasms has been investigated with tumor-bearing animal models. Spontaneous mammary adenocarcinomas of outbred CFW strain Swiss-Webster white mice and chemical carcinogen induced breast tumors in female Sprague-Dawley white rats were clearly visualized in the scintigrams. Mice tissue distribution data demonstrate favourable tumor to organ ratios sufficiently high to permit tumor detection. [99mTc]HPD appears promising as a tumor imaging agent.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1979