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Biomedical subjects

C W Sigel

Publications and source records attributed to C W Sigel.

At least 19 recordsLinked to original sources
PubMed1993

Baquiloprim, a new antifolate antibacterial: in vitro activity and pharmacokinetic properties in cattle.

During examination of the half-lives in cattle of a series of 5-substituted diaminobenzyl-pyrimidines, it was found that replacement of the phenyl ring of trimethoprim (TMP) by bicyclic structures, particularly a quinolyl group, led to increases in half-life. The presence of a dimethylamino group on the quinolyl ring of the compound baquiloprim (BQP) conferred a half-life of about 10 hours. In contrast to TMP (half-life about one hour), BQP was well absorbed from the gastrointestinal tract in all ages of cattle, plasma concentrations reaching a plateau on the day after dosing followed by a slow decline. BQP showed the same high broad spectrum antibacterial activity as TMP, with marked synergy with sulphonamides. Its differential binding of the dihydrofolate reductases of Escherichia coli and rat liver predicted a margin of safety similar to that of TMP. The results of efficacy studies in mice in comparison with TMP showed that the longer half-life of BQP was associated with greater efficacy, and therapeutic properties superior to those of TMP in cattle were therefore predicted for BQP.

Administration, Oral↗
PubMed1991

Metabolism of a novel antitumor agent, crisnatol, by a human hepatoma cell line, Hep G2, and hepatic microsomes. Characterization of metabolites.

Metabolism of the anticancer agent crisnatol was investigated using a human hepatoma cell line, Hep G2, and human liver microsomes. Crisnatol was metabolized extensively by both systems. The TLC/autoradiographic analysis showed that the crisnatol metabolite profile was similar for both systems and the major metabolites were shown to have structural characteristics similar to those formed by the rat. The Hep G2 cells formed three isomeric dihydrodiols; one of these has been identified by GC/MS and 1H-NMR as the crisnatol 1,2-dihydrodiol. Human liver microsomes also formed two isomeric dihydrodiols with 1,2-dihydrodiol as the major isomer and, in addition, produced 1-hydroxycrisnatol. Crisnatol concentrations of 1.3 micrograms/mL completely inhibited the replication of Hep G2 cells as measured by thymidine incorporation and cell growth kinetics and, at this concentration, cell viability decreased by only 35% as determined by vital staining of cells using neutral red dye.

Antineoplastic Agents↗
PubMed1990

High-performance liquid chromatographic assay for the simultaneous measurement of trimethoprim and sulfamethoxazole in plasma or urine.

Procedures for the simultaneous determination of trimethoprim (TMP) and sulfamethoxazole (SMX) in plasma or urine are reported. The drugs are extracted from plasma or urine by a single solid-phase extraction and quantitated by high-performance liquid chromatography. Both drugs are analyzed in the same chromatographic run. Intra- and interassay variability are less than 10% for both compounds, and the recovery and precision of TMP measurement are unaffected by concurrent SMX concentrations. Limits of quantitation for TMP and SMX in plasma were 0.02 and 0.21 microgram/ml, respectively. In urine, the limit of quantitation for both drugs was 1.0 microgram/ml. Metabolites of TMP and SMX did not interfere with the assay. Pharmacokinetic parameters from volunteers given two formulations of co-trimoxazole in a crossover comparison study are reported.

Biological Availability↗
PubMed1989

Competitive protein binding assay for piritrexim.

A competitive protein binding assay for piritrexim (PTX, 1) that makes use of a commercially available radioassay kit for methotrexate has been developed. After it is selectively extracted from plasma, PTX competes with [125l]methotrexate for binding to dihydrofolate reductase isolated from Lactobacillus casei. Free drug is separated from bound drug by adsorption to dextran-coated charcoal. Piritrexim is measurable over a range of 0.01 to 10.0 micrograms/mL in plasma with a coefficient of variation less than 15%. The limit of sensitivity of the assay is approximately 2 ng/mL. An excellent correlation between this assay and a previously published HPLC method was found. published HPLC method was found.

Antineoplastic Agents↗
PubMed1989

2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 13. Some alkenyl derivatives with high in vitro activity against anaerobic organisms.

A series of 2,4-diamino-5-(3,5-dialkenyl-4-methoxy- or -4-hydroxybenzyl)pyrimidines was prepared from [(allyloxy)benzyl]pyrimidines by Claisen rearrangements, and the resulting allyl phenols were further modified by methylation and rearrangement to 1-propenyl analogues. Analogous 3,4-dimethoxy-5-alkenyl derivatives were prepared by similar techniques. High in vitro antibacterial activity was obtained against certain anaerobic organisms, such as Bacteroides species and Fusobacterium, which was equal to or better than the control, metronidazole, in several cases. The profile was similar against Neisseria gonorrhoeae and Staphylococcus aureus. The 3,5-bis(1-propenyl)-4-methoxy derivative 8 was 1 order of magnitude more active against Escherichia coli dihydrofolate reductase than its saturated counterpart, and it was also more active than trimethoprim, 1. However, it was considerably less active in vitro against the Gram-negative organisms. The 3,4-dimethoxy-5-alkenyl, -5-alkyl, and -5-alkoxy analogues had very high broad-spectrum antibacterial activity. However, pharmacokinetic studies of four of the compounds in dogs and rats and in vivo studies with an abdominal sepsis model in rats showed no advantages over trimethoprim.

Alkenes↗
PubMed1988

2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 9. Lipophilic trimethoprim analogues as antigonococcal agents.

Lipophilic analogues of trimethoprim (1) bearing 3,5-dialkyl-4-hydroxy substituents in the benzene ring are much more active in vitro against Neisseria gonorrhoeae than is 1. The 3,5-diisopropyl-4-hydroxy derivative (2) was selected as a candidate for clinical evaluation as an antigonococcal agent, and as part of the preliminary evaluation it was submitted to extended pharmacokinetic and metabolism studies in dogs. Although the compound was not extensively conjugated by metabolic enzymes, one of the methyl groups was metabolized to produce a 3-isopropyl-4-hydroxy-5-(alpha-carboxyethyl)benzyl derivative (43), which was rapidly excreted. Related analogues were likewise extensively metabolized.

Animals↗
PubMed1987

Preclinical biochemical pharmacology and toxicology of piritrexim, a lipophilic inhibitor of dihydrofolate reductase.

Piritrexim (PTX), 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin e, formerly called BW 301U, is a potent small-molecule inhibitor of dihydrofolate reductase (DHFR) that enters cells rapidly by passive diffusion and thus does not depend upon the transport-mediated uptake that can limit cell entry of methotrexate (MTX). PTX is as active as MTX in inhibiting DHFR and mammalian cell growth. In vivo, PTX is active against Walker 256, L1210, P388, Sarcoma 180, and Ehrlich ascites tumors. After iv administration of [14C]PTX to rats, the elimination profile of intact drug from plasma was first order with a half-life (t1/2) of 38 minutes. PTX penetrates extensively into tissues and its tissue:plasma concentration ratios are generally 10-fold higher than those reported for MTX. When administered systemically, PTX inhibits the DHFR-dependent conversion of sepiapterin or 7,8-dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4), demonstrating that PTX enters brain at pharmacologically relevant concentrations. Pharmacokinetic studies in the dog indicated a mean plasma t1/2 (after iv dose) of 2.15 hours, total body clearance of 0.625 liters/hr/kg and steady-state volume of distribution of 1.82 liters/kg; the absolute bioavailability was 0.64. Toxicologic studies were conducted in rats and dogs that received daily doses for 1, 5, or 90 days. In dogs, oral doses of 480 (single dose), 25 (5 daily doses), and 2.5 mg/kg (90 daily doses) were lethal, whereas 240 (single dose), 2.5 (5 daily doses), and 0.5 mg/kg (90 daily doses) produced reversible alterations in clinical toxicity and histopathologic parameters. The lethal toxicity of PTX in dogs given 25 mg/kg/day for 5 days is prevented by oral calcium leucovorin rescue with either 0.75 or 3.0 mg/kg every hour for 4 hours on any of the 5 treatment days. The general pharmacologic profile indicates that PTX should be free of CNS, cardiovascular, and respiratory side effects at clinically useful doses.

Animals↗
PubMed1982

The role of dietary nitrate and nitrite in the reductive deamination of sulfadiazine by the rat, guinea pig, and neonatal calf.

Previous metabolic depletion studies of 14C-sulfadiazine (SDZ) in the neonatal calf led to identification of two novel metabolites, 2-benzenesulfonamidopyrimidine (desNH2SDZ) and 2-benzenesulfonamido-4-hydroxypyrimidine. The novelty of the biotransformation prompted examination of mechanisms for the reductive deamination of SDZ in vivo. In subsequent work, it was found that neonatal calves did not consistently convert SDZ to desNH2SDZ; however, calves that were treated simultaneously with nitrite did. Further, when SDZ was given orally to guinea pigs, whose diet is high in nitrate and who demonstrate the capacity to reduce nitrate to nitrite in the oral cavity, SDZ was transformed to desNH2SDZ. Rats did not reductively deaminate SDZ even if they consumed a diet high in nitrate for two weeks prior to treatment with SDZ. However, they did so when nitrite was added to their diet. These observations strongly suggest that reductive deamination of sulfonamides is dependent on the ingestion of nitrite or the reduction of dietary nitrate to nitrite. This reduction of nitrate to nitrite proceeds in the oral cavity, presumably via microflora residing there.

Animal Feed↗
PubMed1982

Lipid-soluble inhibitors of dihydrofolate reductase. III: Quantitative thin-layer and high-performance liquid chromatographic methods for measuring plasma concentrations of the antifolate, 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido-[2,3-d]pyrimidine.

Specific methods using high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) for the analysis of the potent antifolate, 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido-[2,3-d]pyrimidine (I) in plasma were developed. The HPLC system employed paired-ion chromatography using a mobile phase of water-acetonitrile (65:35, v/v) in conjunction with a reversed-phase C-1 column and detection by UV absorbance measurement. The TLC system utilized a scanning densitometer operating in the reflectance mode with detection of I by fluorescence measurement. The lower limits of detection for the HPLC and TLC methods were approximately 0.005 micrograms/ml. The coefficients of variation for the measurement of drug concentrations over the range of 0.04-1.0 microgram/ml of plasma were 5 and 6%, respectively.

Chromatography, High Pressure Liquid↗
PubMed1982

Evaluation of the lipid-soluble diaminopyrimidines, metoprine and etoprine, in the avian sarcoma virus rat glioma model.

Using the avian sarcoma virus (ASV) rat glioma model, we have evaluated the in vivo effectiveness of two lipid-soluble folate antagonists, metoprine (DDMP) and its 6-ethyl analog etoprine. When adult Fischer 344 rats, which were previously inoculated with ASV as newborns, received DDMP ip, high levels of this drug accumulated in both normal and gliomatous brain tissue, as well as in lung and liver. When animals bearing ASV-induced gliomas were treated with DDMP or etoprine with or without citrovorum factor (calcium leucovorin), there was no increase in survival, even though the drugs were administered at maximally tolerated doses.

Animals↗
PubMed1981

2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 5. 3',5'-Dimethoxy-4'-substituted-benzyl analogues of trimethoprim.

Forty trimethoprim analogues in which the para substituent in the benzene ring was varied were prepared for antibacterial evaluation. All were very potent inhibitors of Escherichia coli dihydrofolate reductase. The similarity of their inhibitory activities strongly suggested that the side chains beyond the first two atoms were not in contact with the enzyme. However, among 38 ether derivatives which varied widely in their bulk and lipophilicity, very few approached trimethoprim in their broad-spectrum in vitro antibacterial activity. The 4'-methyl and 4'-ethyl analogues and the allyloxy and gamma-chloropropoxy ethers had activities fairly close to that of trimethoprim. The two ethers were chosen for further evaluation in vivo. Neither compound quite matched trimethoprim in efficacy in mice, and their half-lives, as well as that of the beta-methoxyethoxy analogue, were found to be shorter in dogs.

Animals↗
PubMed1981

Experimental induction of Proteus mirabilis cystitis in the pony and evaluation of therapy with trimethoprim-sulfadiazine.

Proteus mirabilis cystitis was induced in 9 ponies by chemically eroding the bladder mucosa before the organism was inoculated. Comparisons were made in the treatment of P mirabilis cystitis between ponies treated daily for 13 days with a trimethoprim-sulfadiazine (TMP-SDZ) paste and both positive and negative controls. Urine cultures from ponies treated with TMP-SDZ became negative for P mirabilis between days 3 and 9 after the start of the treatment, whereas positive controls remained infected until day 13. Urine cultures from all ponies were negative for P mirabilis on day 28. Urine concentrations of TMP and SDZ were relatively high after day 1 of therapy.

Administration, Oral↗
PubMed1981

Pharmacokinetics of trimethoprim and sulfadiazine in the dog: urine concentrations after oral administration.

Serial blood samples were obtained from 12 healthy adult dogs given equivalent subcutaneous and oral doses of the antibacterial combination, trimethoprim-sulfadiazine (1:5). By using a 1-compartment open model, pharmacokinetic parameters for both drugs were estimated from the mean serum concentration data after oral administration. Trimethoprim and sulfadiazine were rapidly absorbed, reaching maximum concentrations in 1 and 4 hours with serum elimination half-lives of 2.5 and 9.9 hours, respectively. After a single oral dose (30 mg/kg, combined ingredients) was given, both drugs were present in urine for up to 24 hours at concentrations exceeding the minimum inhibitory concentrations for common pathogenic bacteria.

Administration, Oral↗
PubMed1981

Serum concentrations of trimethoprim and sulfadiazine following oral paste administration to the horse.

Two fasted and 2 fed horses were dosed orally with a combined trimethoprim and sulfadiazine paste formulation at a dose of 35 mg (1:5 combined active ingredients)/kg. Serum concentrations of each drug were determined periodically for 3 consecutive days for the 4 horses. The extent and rate of absorption for trimethoprim were variable, but peak serum concentrations occurred generally within 3 hours; sulfadiazine absorption was slower, reaching peak concentrations by 6 hours. Fasting did not have a consistent effect on the serum concentration profiles for either drug. Both drugs achieved serum concentrations that equaled or exceeded the minimum inhibitory concentrations necessary to inhibit the growth of certain pathogens common to the horse. Thus, the paste formulation provides an effective means of dose administration of horses.

Animals↗
PubMed1980

Synthesis and antitumor activity of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine.

The synthesis of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine (BW301U, 7) by a route that has general applicability to the preparation of many 6-(substituted benzyl)-5-methylpyrido[2,3-d]pyrimidines is described. The key intermediate, 2,4-diamino-7,8-dihydro-6-(2,5-dimethoxybenzyl)-5-methyl-7-oxopyrido[2,3-d]pyrimidine (4), is converted to the 7-chloro compound 5 by treatment with a 1:1 complex of N,N-dimethylformamide--thionyl chloride, and 5 is hydrogenolyzed with palladium on charcoal in the presence of potassium hydroxide to yield 7. BW301U is a potent lipid-soluble inhibitor of mammalian dihydrofolate reductase and has significant activity against the Walker 256 carcinosarcoma in rats.

Animals↗