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Biomedical subjects

R R Streiff

Publications and source records attributed to R R Streiff.

At least 19 recordsLinked to original sources
PubMed2001

Phase 1 study of N1-N11-diethylnorspermine (DENSPM) administered TID for 6 days in patients with advanced malignancies.

UNLABELLED: This was a dose escalation Phase 1 trial designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of DENSPM. METHODS: Adult patients with refractory solid tumors were treated with DENSPM administered by intravenous infusion in 100 ml of normal saline over 30 minutes. The daily dose of DENSPM was divided into three equal doses administered approximately every eight hours for six days. Courses were repeated every 28 days. RESULTS: Twenty-eight patients were enrolled in the study. Dose levels of DENSPM explored were 25 mg/m2/day (3 patients), 50 mg/m2/day (9 patients), 60 mg/m2/day (5 patients), 75 mg/m2/day (6 patients), 94 mg/m2/day (3 patients) and 118 mg/m2/day (2 patients). The DLT for DENSPM was central nervous system toxicity characterized by aphasia, ataxia, dizziness, vertigo and slurred speech occurring at dose levels > or = 94 mg/m2/day, which was also the MTD. SAFETY: The most frequent drug-related adverse events were asthenia (9 patients), injection site reaction (6 patients) and anemia (6 patients). One patient was removed from the study due to CNS toxicity. There were no treatment-related deaths. No trends were observed regarding hematologic toxicities, biochemical changes or changes in vital signs. EFFICACY: Nineteen of the 28 patients enrolled in the study were assessed for response. No objective responses were observed. Five patients had stable disease as the best response to therapy. CONCLUSIONS: Because the DLT was CNS and because of the relatively low doses that could be safely administered on this schedule as compared with a once-a-day schedule, this regimen was not recommended for Phase 2.

Adult↗
PubMed2000

Metabolism and pharmacokinetics of N1,N11-diethylnorspermine in a Cebus apella primate model.

The tissue distribution, metabolic profile, and pharmacokinetic parameters of i.v.-administered N1,N11-diethylnorspermine (DENSPM) are evaluated in Cebus apella primates, and the results are compared with data gathered from canine and human studies. Although the metabolic processing of DENSPM (i.e., deethylation and deaminopropylation) in dogs and primates is very similar, there are some significant differences in tissue distribution of the parent drug. In dogs, the organ concentration of DENSPM follows the order kidney >> liver approximately = lung > spleen. In the primate, the order is liver >> kidney approximately = spleen > lung. The difference in pharmacokinetic parameters between the species is profound with (area under the time-concentration curve)primate << (area under the time-concentration curve)dog; (terminal elimination half-life)primate << (terminal elimination half-life)dog; and (mean residence time)primate << (mean residence time)dog. The most notable difference between dogs and primates is seen in the fraction of parent drug excreted unchanged in the urine, 50% in the dog and < 1% in the primate. However, the pharmacokinetic parameters and urinary drug clearance in C. apella primates are remarkably similar to those in humans. Thus, C. apella is established as an excellent model for assessing the metabolism, tissue distribution, and pharmacokinetic properties of polyamine analogues.

Animals↗
PubMed1995

Metabolism and pharmacokinetics of N1,N11-diethylnorspermine.

The pharmacokinetics and metabolism of N1,N11-diethylnorspermine (DENSPM) is described. When administered to dogs as an intravenous bolus, DENSPM was shown to have a plasma half-life of 72.8 +/- 11.8 min, with an early distribution phase half-life of approximately 4 min and an apparent volume of distribution of 0.216 +/- 0.032 liter/kg. The renal clearance half-life was 59.7 +/- 7.6 min, with 48.8 +/- 12.5% of the drug recovered in the urine between 0-4 hr unchanged. In three other experiments, the drug was administered to dogs by constant rate intravenous infusion over periods ranging from 10 min to 2 hr. Analysis of plasma concentration-time data and urinary excretion data yielded pharmacokinetic parameters in general agreement with the intravenous bolus experiments. DENSPM metabolites were identified in both beagle dog and mouse tissues. Tissues were sampled from a single beagle 24 hr posttreatment, and rodent samples were examined at 12, 24, 48, and 96 hr posttreatment. Both the concentration of DENSPM and the metabolic profile were shown to vary in the lung, liver, spleen, and kidney. Although all the tissues examined contained DENSPM and its metabolites, the liver and kidney had the highest level of metabolites that included N1-ethylnorspermine, N1-ethylnorspermidine, N1-ethyl-1,3-diaminopropane, and norspermidine. These data suggest that DENSPM is metabolized by N-deethylation and step-wise removal of aminopropyl equivalents by spermine/spermidine N1-acetyltransferase/polyamine oxidase, a metabolic pathway unique to the polyamines.

Animals↗
PubMed1993

A comparison of the iron-clearing properties of parabactin and desferrioxamine.

A comparative study of the iron-clearing properties of subcutaneously administered desferrioxamine and parabactin is presented. The evaluation was performed in both a non-iron-overloaded bile-duct cannulated rat and an iron-loaded Cebus monkey model. Parabactin was superior to desferrioxamine in both the rodent and the primate. Unlike desferrioxamine, nearly all of the parabactin-induced iron clearance occurred in the bile. This study represents an evaluation of the iron-clearing properties of parabactin, a hexacoordinate catecholamide siderophore.

Animals↗
PubMed1993

A comparative study of the iron-clearing properties of desferrithiocin analogues with desferrioxamine B in a Cebus monkey model.

A comparative study of the iron-clearing properties of subcutaneously administered desferrioxamine B (DFO) with those of orally administered desferrithiocin sodium salt (1), desmethyl desferrithiocin (2), desazadesmethyl desferrithiocin sodium salt (3), desazadesmethyl desferrithiocin pivaloyloxymethyl ester (4), and desazadesmethyl-5,5-dimethyl desferrithiocin (5) in an iron-loaded Cebus monkey model and a non-iron overloaded bile duct-cannulated rat model is presented. All six drugs, which performed well in rodent studies, demonstrated increased efficiency in the Cebus monkey model. When administered to rodents at a daily dosage of 384 mumol/kg over a period of 10 days, drug 1 demonstrated severe renal toxicity. whereas drugs 3, 4, and 5 exhibited severe gastrointestinal (GI) toxicity. Under the same experimental protocol, drug 2 did not show significant toxic side effects. In addition, to further evaluate the iron-clearing properties of analogue 2, a dose-response study was performed in the primates that showed that iron excretion increased in a dose-dependent fashion.

Animals↗
PubMed1992

A comparison of the iron-clearing properties of 1,2-dimethyl-3-hydroxypyrid-4-one, 1,2-diethyl-3-hydroxypyrid-4-one, and deferoxamine.

A comparative study of the iron-clearing properties of subcutaneously (SC) administered deferoxamine (DFO) with those of orally administered 1,2-dimethyl-3-hydroxypyrid-4-one (CP20) and 1,2-diethyl-3-hydroxypyrid-4-one (CP94) is presented. The studies were performed in both a non-iron-overloaded, bile duct-cannulated rat model and an iron-loaded Cebus monkey model. All three drugs performed well in the rodent, promoting the excretion of iron in both the urine and the bile, with total iron output efficiencies of 2.8%, 1.2%, and 7.1%, respectively. The efficiency of DFO increased slightly in the Cebus model, while that of the hydroxypyridones was essentially the same in the monkey, with total iron output efficiencies of 5.5%, 2.1%, and 7.4%, respectively. Iron balance studies showed that both DFO and CP94 were able to maintain the animals in a negative iron balance, while CP20 had little impact.

Animals↗
PubMed1990

A comparative evaluation of iron clearance models.

A comparative study of the non-iron-overloaded, bile duct-cannulated rat and of the Cebus monkey as iron-clearance models is presented. The ability of desferrioxamine, desferrithiocin, and a pyridoxal isonicotinoyl hydrazone (PIH) analogue to clear the metal from these two animals is evaluated. Data suggest that although rodents represent a viable first-line animal screen, there is no strict correspondence between the effectiveness of a chelator in rodents and that in primates. Rodent data should be interpreted carefully as it relates to potential human trials. Iron-loading response, the similarity between multiple human and Cebus serum and hematological values, and the ability to easily observe changes in behavioral patterns clearly render the Cebus monkey the best preclinical screen.

Animals↗
PubMed1985

Influence of iron on in vivo proliferation and lethality of L1210 cells.

The ability of iron to stimulate the growth of L1210 cells both in DBA-2 mice and in cell culture is evaluated. Although in vitro stimulation is absent, in vivo studies clearly indicate higher numbers of tumor cells in the presence of supplemental iron. When mice were given iron i.p., at levels comparable to clinical doses for humans (24 mg/kg body weight), the tumor load recovered from their peritoneum was substantially greater than from controls without iron supplements. Furthermore, at higher levels of supplemental iron (250 mg Fe/kg body weight), the pretreated animals inoculated with L1210 cells died in 9.7 d whereas controls died in 12.2 d (i.e., 25% faster). As expected, the lower iron dose (24 mg/kg) also resulted in shorter life spans, although the effects were less striking. It is the belief of these authors that these data support the opinion that "anemia of chronic disease" associated with leukemia and possibly other malignancies may represent a host defense mechanism as has been postulated by others (1, 8).

Animals↗
PubMed1983

The effect of diphenylhydantoin (phenytoin) on the sequential stages of intestinal folate absorption.

The drug diphenylhydantoin (phenytoin) (DPH) is thought to interfere with the bioavailability of dietary folate through an effect on intestinal folate deconjugation and/or monoglutamate folate transport. In order to determine whether DPH inhibition occurs in the sequential steps of folate deconjugation, uptake, or reduction-methylation, the effect of the drug on the intestinal absorption of hexaglutamate folate (PteGlu6), pteroylmonoglutamate folate (PGA), and N-5-methyltetrahydrofolate (CH3FH4) was studied. Folate absorption was directly quantified by the method of triple lumen tube perfusion in 12 subjects serving as their own controls. All 12 received PGA mixed with and without DPH (20 micrograms/ml), while 6 of the 12 subjects received hexaglutamate and 6 received reduced methylated folate with and without added DPH. With this model DPH was shown not to impair significantly folate absorption by any action upon the process of folate deconjugation, absorption, or reduction-methylation. The previously reported association between DPH intake and reduced levels of serum folate remains unexplained by these studies.

Adult↗
PubMed1980

Erythrocytosis associated with carboxyhemoglobinemia in smokers.

During a two-year period, we evaluated 14 patients with erythrocytosis. Carboxyhemoglobinemia secondary to cigarette or cigar smoking or both caused elevated hematocrit values in ten of the patients, and in all 14 either red cell volume was increased or plasma volume was decreased. There was no correlation between the number of cigarettes or cigars reportedly smoked and either the degree of carboxyhemoglobinemia or the hematocrit value, In three patients who stopped smoking permanently, hematocrit values decreased from a mean of 56% to 46%. Even though the high hematocrit value reversed when these patients stopped smoking, we met with limited success in persuading the others to do so.

Adult↗
PubMed1979

Folate antagonism following teratogenic exposure to diphenylhydantoin.

Previous studies have reported indirect evidence for the mediation of folate antagonism in the induction of malformations by diphenylhydantion. We have demonstrated that a teratogenic regimen of folate-deficiency and antagonism using 9-methyl PGA in the rat produces significantly decreased rates of oxygen consumption in the maldeveloping embryos. The present study reports similar reductions in oxygen uptake by mouse embryos from mothers treated with teratogenic doses of diphenylhydantoin, and documents a significant depression of the actual folate levels in such embryos. The differences are less significant with lower doses of diphenylhydantoin, and do not occur with a nonteratogenic dose.

Abnormalities, Drug-Induced↗
PubMed1978

Effect of diphenylhydantoin on the bioavailability of citrus folate.

Long term use of the drug diphenylhydantoin (DPH) has been associated with biochemical evidence of folic acid deficiency and rarely with megaloblastic anemia. The mechanism of this nutritional deficiency is uncertain but is thought to result from DPH-induced alteration in the intestinal absorption of conjugated and/or free dietary folate. The effect of DPH on the intestinal absorption of free folates from a food source has heretofore not been reported. In this study triple lumen tube perfusion of the human jejunum was used to quantitate folate absorption from a control solution of orange juice and from an identical solution containing DPH. The results in eleven volunteers serving as their own controls indicate no effectof DPH at a concentration of 20 microgram/ml on folate absorption from this food source. The predominant form of folate in orange juice as determined by differential microbiologic assay is N-5-methyltetrahydrofolate. DPH does not appear to interfere with the absorption of free food folate which is both methylated and reduced.

Adult↗
PubMed1975

Comparative bioavailability of folate and vitamin C from a synthetic and a natural source.

Intraluminal perfusion of the human small intestine has not been used extensively to study comparative bioavailability of vitamins. In this study a triple lumen tube with a 30-cm study segment was used to measure absorption of water-soluble vitamins from the human proximal jejunum. Fifteen normal subjects served as their own controls to quantitate absorption of folic acid and vitamin C from an orange juice solution and from a solution of synthetic vitamins. Despite a predictably greater water absorption from the glucose containing orange juice solution, the absorption of the two water-soluble vitamins did not differ significantly from the two solutions. Natural and synthetic ascorbate and folate were avidly absorbed in the first 30 cm of jejunum and with the exception of synthetic folate correlated positively with water absorption. This method, previously applied to the absorption of sugars, amino acids, and electrolytes, can be reliably applied to the study of comparative bioavailability of nutrients from food sources. The advantages of triple lumen perfusion over previous methods are: 1) it overcomes the necessity for urine collections in metabolic studies, 2) it can be used to study sites and mechanism of absorption, and 3) it is a direct measurement of absorption capacity.

Adult↗