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Biomedical subjects

G Eckhardt

Publications and source records attributed to G Eckhardt.

15 recordsLinked to original sources
PubMed2000

Population pharmacokinetics/toxicodynamics (PK/TD) relationship of SAM486A in phase I studies in patients with advanced cancers.

SAM486A (previously termed CGP 48664), a potent inhibitor of S-adenosylmethionine decarboxylase, is under clinical development for the treatment of advanced refractory malignancies. Hematological toxicity manifested by dose-dependent neutropenia has been observed in phase I studies. Population methods were used to investigate pharmacokinetics (PK) as a prognostic factor for safety end point (hematological toxicity) in patients with advanced cancers. SAM486A plasma concentrations and neutrophil counts were collected from three ascending-dose tolerability and PK studies (study 1: single 5-day continuous intravenous (IV) infusion with doses ranging from 24-700 mg/m2/cycle; study 2: 10-minute to 3-hour IV infusion once weekly with doses ranging from 16-325 mg/m2/week; study 3: 1-hour IV infusion once daily for 5 days with doses ranging from 3.6-202.8 mg/m2/day). The PK of SAM486A were best estimated by a population linear three-compartment model with NONMEM (version 5) using data from 9 patients in studies 1 through 3. The population pharmacokinetic parameters (SD) were CL = 6.2 (0.4) l/h/m2, Q2 = 15.4 (1.5) l/h/m2, Q3 = 33.6 (5.3) l/h/m2, V1 = 9.5 (1.6) l/m2, V2 = 672 (52) l/m2, and V3 = 39.9 (8.3) l/m2, and the corresponding intersubject variability was 45.4%, 74.0%, 85.3%, 80.1%, 37.0%, and 103%, respectively, where CL is total body clearance, Q2 and Q3 are intercompartmental clearances, and V1, V2, and V3 are the volumes of distribution in central and peripheral compartments, respectively. The intrasubject variability was 24.0%. The cumulative AUC before the onset of neutrophil nadir count (AUC) and the duration of exposure over threshold SAM486A concentrations in the range of 0.05 to 0.1 microM based on Bayesian PK parameter estimates significantly correlated with absolute neutrophil count nadir (< 5 x 10(9)/l). AUC showed the best correlation (R2 = 0.72) with absolute neutrophil count nadir by an inhibitory sigmoid Emax model and also correlated with percent decrease in neutrophil count from baseline to nadir by a simple Emax model (R2 = 0.53). Logistic regression analysis indicated that AUC and the duration of exposure over 0.05 to 0.1 microM, but not Cmax, were strong predictors of grade 4 neutropenia (< 0.5 x 10(9)/l). Drug exposure parameters such as AUC derived from population analysis may be used clinically as a useful predictor of drug-induced neutropenia.

Adult↗
PubMed2000

A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer.

An E1B 55 kDa gene-deleted adenovirus, Onyx-015, which reportedly selectively replicates in and lyses p53-deficient cells, was administered by a single intratumoral injection to a total of 22 patients with recurrent head and neck cancer. The objectives of this Phase I study were to determine the safety, feasibility, and efficacy of this therapy and determine any correlation to p53 status. Six cohorts were investigated with a dose escalation from 10(7)-10(11) plaque-forming units. Toxicity was assessed using NCIC criteria. Tumor response was assessed by clinical and radiological measurement. Blood samples were taken to detect adenovirus DNA and neutralizing antibody to adenovirus. Tumor biopsies were taken to detect adenovirus by in situ hybridization. Treatment was well tolerated, with the main toxicity being grade 1/2 flu-like symptoms. Dose-limiting toxicity was not reached at the highest dose of 10(11) plaque-forming units. Twenty-one of the 22 patients treated showed an increase in neutralizing antibody to adenovirus. In situ hybridization showed viral replication in 4 of 22 patients treated, all of whom had mutant p53 tumors. Using conventional response criteria, no objective responses were observed. However, magnetic resonance imaging scans were suggestive of tumor necrosis at the site of viral injection in five patients, three of whom were classified using nonconventional criteria as partial responders, and two of whom were classified using nonconventional criteria as minor responders. Of these five cases, four had mutant p53 tumors. The response duration for the three partial responders was 4, 8, and 12 weeks. An additional eight patients had stable disease in the injected tumors lasting from 4-8 weeks. These preliminary results show that intratumoral administration of Onyx-015 is feasible, well tolerated, and associated with biological activity. Further investigation of Onyx-015, particularly with a more frequent injection protocol and in combination with systemic chemotherapy, is warranted.

Adenovirus E1B Proteins↗
PubMed1998

In vitro antitumor activity of the novel marine agent, ecteinascidin-743 (ET-743, NSC-648766) against human tumors explanted from patients.

BACKGROUND: Ecteinascidin-743 (ET-743), a member of the ecteinascidin family selected for clinical development, is a tetrahydroisoquinolone alkaloid isolated from the marine ascidian, Ecteinascidia turbinata. This novel compound is a minor groove binding, guanine-specific alkylating agent which also interacts with the microtubule network and blocks cell cycle progression at late S/G2. MATERIALS AND METHODS: A soft agar cloning assay was used to determine the in vitro effects of ET-743 against primary human tumor specimens taken directly from patients. A total of 93 evaluable specimens were exposed to ET-743 for one-hour (n = 25) and/or 14-day continuous exposure (n = 92) at concentrations ranging from 0.1 nM to 1 microM. In vitro responses were defined as an inhibition > or = 50% of human tumor colony forming units at a given concentration. RESULTS: One-hour exposure to ET-743 at concentrations of 0.1 nM, 1 nM, 10 nM, 100 nM and 1 microM induced in vitro responses in 0% (0/17), 6% (1/17), 16% (4/25), 13% (1/8), and 25% (2/8) of specimens, respectively. Continuous exposure to ET-743 at concentrations of 0.1 nM, 1 nM, 10 nM, 100 nM and 1 microM, inhibited 0% (0/16), 13% (2/16), 49% (44/90), 62% (47/76), and 77% (58/75) of tumor specimens, respectively. Tumor-specific responses and concentration-dependent relationships were observed with a continuous exposure to ET-743. At 100 nM, the compound inhibited 79% (11/14) breast, 69% (9/13) non-small-cell lung, 58% (7/12) ovary, and 88% (7/8) melanoma specimens. At 1 microM, ET-743 inhibited 100% (14/14) breast specimens, 85% (11/13) non-small-cell lung, 67% (8/12) ovary and 86% (6/7) melanoma specimens. Activity of ET-743 at and above 10 nM was also observed against sarcoma and kidney tumors. At 10 nM concentration and continuous exposure ET-743 demonstrated incomplete cross-resistance with paclitaxel, alkylating agents, doxorubicin and cisplatin. CONCLUSIONS: Our data from the cloning assay indicate that the duration of exposure to ET-743 is an important factor in human tumors. Therefore, long-term exposure to ET-743 may be preferred in future clinical trials. The activity of ET-743 in breast, non-small-cell lung, and ovarian cancers as well as in melanoma may deserve further clinical evaluations. The potential of ET-743 in sarcoma and renal tumors might also be considered. In addition, our data indicate that a plasma concentration of 100 nM of ET-743 must be considered as a target during the clinical development of the compound; also the concept of continuous/protracted exposure in clinical trials with ET-743 has to be taken into account.

Animals↗
PubMed1995

New anticancer agents in clinical development.

A better understanding of the biology and biochemistry of the cancer cell has led to the development of various promising new antineoplastic compounds that are now undergoing phase I, II, and III clinical testing. These drugs include topoisomerase I inhibitors, such as camptothecin and its analogs 9-aminocamptothecin, irinotecan, and topotecan; the paclitaxel analog docetaxel; gemcitabine, an antimetabolite structurally related to cytarabine; and fluorouracil prodrugs and other thymidylate synthase (TS) inhibitors. Another exciting approach to cancer treatment is the use of agents that induce a less malignant state by altering cellular phenotype. Such agents include angiogenesis inhibitors, differentiating agents, signal transduction inhibitors, and gene therapy.

Antimetabolites, Antineoplastic↗
PubMed1995

New anticancer agents in clinical development.

A better understanding of the biology and biochemistry of the cancer cell has led to the development of various promising new antineoplastic compounds that are now undergoing phase I, II, and III clinical testing. These drugs include topoisomerase I inhibitors, such as camptothecin and its analogs 9-aminocamptothecin, irinotecan, and topotecan; and the paclitaxel analog docetaxel. The authors discussed these new agents last month. In Part 2 of their article, they describe gemcitabine, an antimetabolite structurally related to cytarabine; fluorouracil prodrugs and other thymidylate synthase (TS) inhibitors, and new approaches to anticancer therapy, such as angiogenesis inhibitors, differentiating agents, signal transduction inhibitors, and gene therapy.

Antimetabolites, Antineoplastic↗
PubMed1993

Two new antiinflammatory elemanolides from Centaurea chilensis.

Two previously undescribed elemanolide esters, the 2-methylpropanoate and 2-methyl-2-propenoate of 11,13-dehydromelitensin, were isolated in the course of a bioassay-guided fractionation from the aerial parts of Centaurea chilensis Hook. et Arn., used traditionally to treat 'gout and rheumatism'. The mixture of both substances exhibits anti-inflammatory activity in the carrageenan-induced paw edema assay.

Animals↗
PubMed1984

[HDL and LDL cholesterol changes in psychological stress in relation to stress experience].

During examinations and after a three-month examination period the changes of the parameters of fat metabolism were investigated depending upon stress experience before examinations. Students with a distinct stress experience showed a higher total cholesterol and LDL-cholesterol as well as a higher LDL/HDL-cholesterol quotient within a concrete examination. After the examination period in this group a higher LDL/HDL-cholesterol quotient and a lower HDL-cholesterol level was established in comparison to the group with an insignificant stress experience. A positive dependence on the initial value of the parameters of fat metabolism consists only in the group with distinct stress experience. According to these results also stress has an influence on the reactions of the fractions of cholesterol.

Adult↗
PubMed1980

[Amino acid losses in human sweat. Influence of oral contraceptives, physical exercise and sex on the excretion of amino acids in sweat (author's transl)].

UNLABELLED: With the aid of ion exchange column chromatography we determined quantitatively the free amino acids in thermal sweat of the total human body surface. Sweat of 60 healthy men and 63 healthy women (aged 18-31 years) collected during 12 min of sauna bathing was investigated. Thirty men and 31 women were well trained, 33 women were taking oral, hormonal contraceptives. Sweat was deproteinised by adding an equal volume of 5% sulphosalicylic acid. RESULTS: 1. The comparison of the women taking oral contraceptives with the women not taking oral contraceptives showed no qualitative or significant quantitative differences in the excretion of amino acids in thermal sweat collected from the total body surface. 2. The comparison of the trained women with the untrained women neither revealed qualitative or significant quantitative differences in the excretion of amino acids in thermal sweat collected from the total body surface. 3. As compared to the trained men, untrained men excreted in thermal sweat collected from the total body surface significantly more alanine, arginine, citrulline, cystine, glycine, histidine, isoleucine, leucine, lysine, phenylalanine, serine, threonine, tyrosine, and valine. 4. The sex-specific comparison of the amino acid excretion in sweat showed that men had a significantly increased excretion of cystine, histidine, leucine, and taurine. Proline was detected only in the sweat of women. 5. The quantitative results obtained for the amino acid excretions during 12 min of sauna bathing suggest that persons exposed to hard, physical activity and/or high environmental temperatures have quite equal amino acid losses in sweat and in 24 h urine.

Adolescent↗
PubMed1980

[Isolation and identification of some metabolites of bromazine from human urine (author's transl)].

In addition to the unchanged drug nine metabolites have been found in human urine after the administration of bromazine (2-(p-bromophenyl-phenylmethoxy)-1-N,N-dimethyl-ethylamine). Three compounds were extractable under alkaline conditions; they were identified as bromazine-N-oxide (II), N-monodesmethylbromazine (III) and N-didesmethylbromazine (IV). Two other substances were extractable under alkaline and acidic conditions, p-bromobenzhydrol (VI) and p-bromobenzophenone (VIII). Another metabolite--extractable at pH 7--was p-hydroxybenzophenone (IX). Treatment of precipitated conjugated compounds with beta-glucuronidase or hydrochloric acid resulted in the liberation of IV, VI and IX, all of which were also found as unconjugated compounds.

Biotransformation↗
PubMed1977

[Isolation and identification of some metabolites of mephenoxalone (Control-OM) from human urine (author's transl)].

Mephenoxalone (5-(o-methoxyphenoxymethyl)-2-oxazolidone) is degraded by various routes in the human, and some is excreted unchanged. In the metabolism of mephenoxalone, the phenoxymethyl ether bond is cleaved; thus o-methoxyphenol (metabolite I) was identified in urine, and 3-amino-1,2-propanediol (IIa) was found after alkaline hydrolysis. Hydroxylation of the benzene ring produces a phenolic hydroxymephenoxalone (metabolite III), and demethylation converts mephenoxalone into demethylmepheonxalone (metabolite IV). Opening of the oxazolidone ring leads to the production of 1-(o-methoxyphenoxy)-3-aminopropane-2-ol(metabolite V). Urine contains two further substances: 1-(o-hydroxyphenoxy)-3-aminopropene (metabolite VI) and dehydromephenoxalone (metabolite VII). Metabolite VI may be an artefact. Compounds III, IV and VII could only be detected after acid hydrolysis and enzymic cleavage with beta-glucuronidase/aryl sulphatase, whereas V and VI were detected only after acid hydrolysis. Thin layer chromatography revealed three further metabolites, which were not identified.

Adult↗
PubMed1977

[Isolation and structure determination of the metabolites of 2-(1,3-dimethyl-xanthinyl-(7)-methyl)-4-methyl-morpholine--a xantinol derivative--from rat urine (author's transl)].

In the urine of rats the following metabolites of the xantinol derivative 2-(1,3-dimethyl-xanthinyl-(7)-methyl)-4-methyl-morpholine were found: 2-[1,3-dimethyl-xanthinyl-(7)-methyl]-morpholine and 2-[1,3-dimethyl-xanthinyl-(7)-methyl]-4-methyl-morpholin-5-one. These compounds represent about 13.7% of the p.o. applied 2-[1,3-dimethyl-xanthinyl-(7)-methyl]-4-methyl-morpholine. Their structure has been elucidated by IR-, PMR- and mass spectrometry.

Animals↗
PubMed1977

[Isolation and identification of some metabolites of clofedanol from human urine (author's transl].

10 excretory products of Clofedanol (1-(o-chlorphenyl)-1-phenyl-3-dimethylaminopropanol) were identified in human urine. The following five products were extracted with chloroform at pH 1--2: o-(chlorphenyl)-phenylmethane (I), benzophenone (II), o-chlorbenzophenone (III), benzhydrol (IV), and o-(chlorphenyl)-beta-phenylacrolein (V). Two compounds were extracted with chloroform at pH 13--14: unchanged Clofedanol and 1-(o-chlorphenyl)-1-phenyl-3-dimethylaminopropene-1 (VI). N,N-dimethylamino-acetic acid (VII) was also identified in urine. Clofedanol and metabolite IV were present as free compounds, and they were also found after hydrolysis of metabolites VIII and IX with beta-glucuronidase.

Antitussive Agents↗
PubMed1977

[Isolation and identification of some metabolites of phenyramidol (Cabral) from human urine (author's transl)].

The biological transformation of phenyramidol (I), some of which is also excreted unchanged, occurs by three main degradative pathways: 1. Hydroxylation of the pyridine ring in position 3 (metabolite V) and 5 (metabolite VI). 2. Cleavage of the ethanolamine chain with the formation of 2-aminopyridine (metabolite II) and presumably mandelic aldehyde. 3. Conjugation with glucuronic acid (metabolite III). Secondary reactions result in the production of: benzoyl carbinol (metabolite XV), benzoic acid (metabolite XI), mandelic acid (metabolite XII) and the glucuronides of V, VI, VII, XII and possibly II (metabolites VIII, IX, X, XIII and IV), all of which were also found as free, unconjugated compounds. A further, unusual reaction is the dimerisation of metabolite VI with the formation of a dipyridyl derivative (metabolite VII), which is excreted partly as the free compound, but mainly as the glucuronide (metabolite X). The occurrence of 2-(N-benzylamino)-pyridine (XIV) in the urine could not be explained. Four futher excretory products (metabolites XVI, XVII, XVIII and XIX) were not identified; XVI and XVII were extracted at an alkaline pH, whereas XVIII and XIX were extracted under neutral conditions. They could be detected both as free compounds, and after hydrolysis with HCl or alkali, but not after treatment with beta-glucuronidase.

Adult↗
PubMed1976

[Isolation and structure determination of metabolites of xantinol from rat urine (author's transl)].

In the urine of rats as metabolites of the theophylline-derivative 7-[2-hydroxy - 3 - (N-methyl-N-2-hydroxyethyl)-amino-propyl]-1,3-dimethylxanthine (xantinol), the two stereoisomeric 2-coffeinyl-N-methyl-6-hydroxy-morpholines were found. These compounds represented about 7 to 8 percent of the eliminated xantinol and can be described structurally as semiacetals of a terminal aldehyde formed from Xantinol. Their structure has been elucidated by combined NMR- and mass-spectrometry. After oral application of xantinol-nicotinate in therapeutic doses to male test subjects, the same substances were detected by thin-layer chromatography. Both compounds could be synthetized by treatment of 7-[2,3-epoxypropyl]-theophylline or 7-[2-hydroxy-3-chloro-propyl]-theophylline with methylami-noacetaldehyde-dimethylacetal and subsequent hydrolysis of the reaction product with hydrochloric acid.

Animals↗