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Antimicrobial Agents and Chemotherapy May 1996Zidovudine is widely prescribed for the treatment of human immunodeficiency virus (HIV) infection. Trimethoprim and dapsone are commonly used in the management of... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Zidovudine is widely prescribed for the treatment of human immunodeficiency virus (HIV) infection. Trimethoprim and dapsone are commonly used in the management of Pneumocystis carinii pneumonia in HIV-infected patients. To examine the pharmacokinetic interactions among these drugs, eight HIV-infected patients (26 to 43 years old) with a mean CD4 count of 524.4 +/- 405.7 cells per mm3 received zidovudine (200 mg), trimethoprim (200 mg), and dapsone (100 mg) as single agents and in two- and three-drug combinations. Blood and urine samples were collected at a specified time and analyzed for zidovudine, zidovudine-glucuronide, trimethoprim, dapsone, and monoacetyl-dapsone concentrations under single-dose and steady-state conditions. Zidovudine did not influence the pharmacokinetic disposition of dapsone or trimethoprim. Dapsone had no effect on the pharmacokinetic disposition of zidovudine. Trimethoprim significantly decreased the renal clearance of zidovudine by 58% (5.0 +/- 1.8 versus 2.1 +/- 0.5 ml/min/kg of body weight [P < 0.05]). There was a concurrent 54% decrease in the mean urinary recovery of zidovudine (11.7 +/- 3.5 versus 5.4 +/- 3.0 [P < 0.05]), and the metabolic ratio was decreased by 78% (0.32 +/- 0.4 versus 0.07 +/- 0.05 [P < 0.05]). The mean area under the concentration-time curve from 0 to 6 h of the zidovudine-glucuronide/ zidovudine ratio was unchanged. We conclude that zidovudine, trimethoprim, and dapsone can be coadministered to patients with AIDS without significant pharmacokinetic interaction. However, in AIDS patients with liver impairment and impaired glucuronidation, doses of zidovudine may need to be decreased.
Topics: Acquired Immunodeficiency Syndrome; Adult; Dapsone; Drug Combinations; Humans; Male; Trimethoprim; Zidovudine
PubMed: 8723472
DOI: 10.1128/AAC.40.5.1231 -
ACS Chemical Biology Jan 2021Cell-cell interactions and communication are crucial to the proper function of complex mammalian physiology including neurocognitive and immune system functions. While...
Cell-cell interactions and communication are crucial to the proper function of complex mammalian physiology including neurocognitive and immune system functions. While many tools are available for observing and perturbing intracellular processes, relatively few exist to probe intercellular processes. Current techniques for studying interactions often rely on direct protein contact, and few can manipulate diverse, functional outputs with tunable protein expression. To address these limitations, we have developed a small-molecule approach based on a trimethoprim prodrug-enzyme pair capable of reporting the presence of two different engineered cell populations with programmable protein outputs. The approach relies on bacterial nitroreductase enzyme catalysis, which is orthogonal to normal mammalian biology, and diffusion of trimethoprim from "activator" cells to "receiver" cells. We test this strategy, which can theoretically regulate many different types of proteins, using biochemical and culture assays with optical and cytokine protein readouts. This describes the first small-molecule approach capable of detecting and controlling engineered cell-cell outputs, and we anticipate future applications that are especially relevant to the field of immuno-oncology.
Topics: Animals; Cell Communication; Cell Engineering; Coculture Techniques; Dose-Response Relationship, Drug; Luciferases, Firefly; Prodrugs; Proteins; Small Molecule Libraries; Trimethoprim
PubMed: 33351606
DOI: 10.1021/acschembio.0c00935 -
PloS One 2018Metabolomics-based approaches were applied to understand interactions of trimethoprim with Escherichia coli K-12 at sub-minimum inhibitory concentrations (MIC≈0.2,...
Metabolomics-based approaches were applied to understand interactions of trimethoprim with Escherichia coli K-12 at sub-minimum inhibitory concentrations (MIC≈0.2, 0.03 and 0.003 mg L-1). Trimethoprim inhibits dihydrofolate reductase and thereby is an indirect inhibitor of nucleic acid synthesis. Due to the basicity of trimethoprim, two pH levels (5 and 7) were selected which mimicked healthy urine pH. This also allowed investigation of the effect on bacterial metabolism when trimethoprim exists in different ionization states. UHPLC-MS was employed to detect trimethoprim molecules inside the bacterial cell and this showed that at pH 7 more of the drug was recovered compared to pH 5; this correlated with classical growth curve measurements. FT-IR spectroscopy was used to establish recovery of reproducible phenotypes under all 8 conditions (3 drug levels and control in 2 pH levels) and GC-MS was used to generate global metabolic profiles. In addition to finding direct mode-of-action effects where nucleotides were decreased at pH 7 with increasing trimethoprim levels, off-target pH-related effects were observed for many amino acids. Additionally, stress-related effects were observed where the osmoprotectant trehalose was higher at increased antibiotic levels at pH 7. This correlated with glucose and fructose consumption and increase in pyruvate-related products as well as lactate and alanine. Alanine is a known regulator of sugar metabolism and this increase may be to enhance sugar consumption and thus trehalose production. These results provide a wider view of the action of trimethoprim. Metabolomics indicated alternative metabolism areas to be investigated to further understand the off-target effects of trimethoprim.
Topics: Anti-Bacterial Agents; Chromatography, Liquid; Dose-Response Relationship, Drug; Escherichia coli K12; Hydrogen-Ion Concentration; Mass Spectrometry; Microbial Sensitivity Tests; Trimethoprim
PubMed: 30005078
DOI: 10.1371/journal.pone.0200272 -
Molecules (Basel, Switzerland) Nov 2021In this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for...
In this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for 2,4-diaminopyrimidine (DAP), which is the pharmacophore of these active pharmaceutical ingredients (API). The isomeric pyridinecarboxamides and two xanthines, theophylline (THEO) and caffeine (CAF), were used as co-formers in the same experimental conditions, in order to evaluate the potential for the pharmacophore to be used as a guide in the screening process. In silico co-crystal screening was carried out using BIOVIA COSMOquick and experimental screening was performed by mechanochemistry and supported by (solid + liquid) binary phase diagrams, infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). The in silico prediction of low propensities for DAP, TMP and PMA to co-crystallize with pyridinecarboxamides was confirmed: a successful outcome was only observed for DAP + nicotinamide. Successful synthesis of multicomponent solid forms was achieved for all three target molecules with theophylline, with DAP co-crystals revealing a greater variety of stoichiometries. The crystalline structures of a (1:2) TMP:THEO co-crystal and of a (1:2:1) DAP:THEO:ethyl acetate solvate were solved. This work demonstrated the possible use of the pharmacophore of DHFR inhibitors as a guide for co-crystal screening, recognizing some similar trends in the outcome of association in the solid state and in the molecular aggregation in the co-crystals, characterized by the same supramolecular synthons.
Topics: Crystallography, X-Ray; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Models, Molecular; Molecular Structure; Pyrimethamine; Pyrimidines; Tetrahydrofolate Dehydrogenase; Trimethoprim
PubMed: 34771128
DOI: 10.3390/molecules26216721 -
Microbiological Reviews Jun 1981
Review
Topics: Anti-Bacterial Agents; Bacteria; Biological Evolution; Drug Resistance, Microbial; Genes; Mutation; R Factors; Salmonella typhimurium; Selection, Genetic; Trimethoprim
PubMed: 7022157
DOI: 10.1128/mr.45.2.355-378.1981 -
Journal of Clinical Microbiology Jan 2017Antimicrobial susceptibility test results for trimethoprim-sulfadiazine with Streptococcus equi subspecies are interpreted based on human data for...
Evaluation of Veterinary-Specific Interpretive Criteria for Susceptibility Testing of Streptococcus equi Subspecies with Trimethoprim-Sulfamethoxazole and Trimethoprim-Sulfadiazine.
Antimicrobial susceptibility test results for trimethoprim-sulfadiazine with Streptococcus equi subspecies are interpreted based on human data for trimethoprim-sulfamethoxazole. The veterinary-specific data generated in this study support a single breakpoint for testing trimethoprim-sulfamethoxazole and/or trimethoprim-sulfadiazine with S. equi This study indicates trimethoprim-sulfamethoxazole as an acceptable surrogate for trimethoprim-sulfadiazine with S. equi.
Topics: Animals; Anti-Bacterial Agents; Drug Combinations; Microbial Sensitivity Tests; Streptococcus equi; Sulfadiazine; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Veterinary Medicine
PubMed: 27847375
DOI: 10.1128/JCM.01610-16 -
Environment International Nov 2020Antibiotic resistance presents a serious and still growing threat to human health. Environmental exposure levels required to select for resistance are unknown for most...
Antibiotic resistance presents a serious and still growing threat to human health. Environmental exposure levels required to select for resistance are unknown for most antibiotics. Here, we evaluated different experimental approaches and ways to interpret effect measures, in order to identify what concentration of trimethoprim that are likely to select for resistance in aquatic environments. When grown in complex biofilms, selection for resistant E. coli increased at 100 µg/L, whereas there was only a non-significant trend with regards to changes in taxonomic composition within the tested range (0-100 µg/L). Planktonic co-culturing of 149 different E. coli strains isolated from sewage again confirmed selection at 100 µg/L. Finally, pairwise competition experiments were performed with engineered E. coli strains carrying different trimethoprim resistance genes (dfr) and their sensitive counterparts. While strains with introduced resistance genes grew slower than the sensitive ones at 0 and 10 µg/L, a significant reduction in cost was found already at 10 µg/L. Defining lowest effect concentrations by comparing proportion of resistant strains to sensitive ones at the same time point, rather than to their initial ratios, will reflect the advantage a resistance factor can bring, while ignoring exposure-independent fitness costs. As costs are likely to be highly dependent on the specific environmental and genetic contexts, the former approach might be more suitable as a basis for defining exposure limits with the intention to prevent selection for resistance. Based on the present and other studies, we propose that 1 µg/L would be a reasonably protective exposure limit for trimethoprim in aquatic environments.
Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Escherichia coli; Humans; Trimethoprim; Trimethoprim Resistance
PubMed: 32890888
DOI: 10.1016/j.envint.2020.106083 -
Antimicrobial Agents and Chemotherapy Jan 1981Various sulfonamides and trimethoprim were given orally twice a day to healthy volunteers. The drug concentrations in serum and tissue fluid from skin blisters were...
Various sulfonamides and trimethoprim were given orally twice a day to healthy volunteers. The drug concentrations in serum and tissue fluid from skin blisters were determined concomitantly. Maximal serum concentrations were obtained after 1 to 3 h. Absorption of sulfacarbamide and sulfadimidine was more rapid than for sulfadiazine, sulfamethoxazole, and trimethoprim. The penetration to blister fluid was delayed and maximal concentrations were usually reached after 4 to 8 h. The highest penetration to blister fluid was found for sulfacarbamide, sulfadiazine, and trimethoprim. During maintenance therapy sulfadiazine and trimethoprim gave blister fluid concentrations usually above 50% of the serum level. However, on the basis of dosage the highest sulfonamide concentration both in serum and blister fluid was obtained with sulfamethoxazole.
Topics: Adult; Blister; Exudates and Transudates; Female; Humans; Kinetics; Male; Skin; Sulfonamides; Time Factors; Trimethoprim
PubMed: 7247364
DOI: 10.1128/AAC.19.1.82 -
Canadian Journal of Veterinary Research... Oct 1996Healthy gilts and market-ready hogs were administered a single intramuscular (IM) injection of Borgal, a commercial formulation of trimethoprim-sulfadoxine (TMP-SDX),...
Healthy gilts and market-ready hogs were administered a single intramuscular (IM) injection of Borgal, a commercial formulation of trimethoprim-sulfadoxine (TMP-SDX), once or twice daily. The objectives were to determine if a newly-developed high-performance liquid chromatographic (HPLC) method would be suitable for measuring the residual concentrations of TMP in the plasma of these live animals, and to determine if the administration of this veterinary drug would leave measurable residues in their plasma and tissues at slaughter. Plasma and tissue concentrations of SDX and TMP from these animals were determined over a period of 14 d using thin-layer chromatography/densitometry (TLCD), and the newly-developed HPLC method, respectively. The lowest detectable limit (LDL) for SDX in plasma and tissue was 20 ppb by TLCD. The HPLC method had a LDL of 5 ppb for TMP in plasma and tissue. Both methods were then used to provide baseline data on the absorption and depletion of TMP and SDX from these healthy animals. It was observed that both TMP and SDX were readily absorbed into the blood and tissues, but TMP was eliminated much faster than SDX. No TMP residues were detected in the plasma of any of the gilts at and beyond 21 h after drug administration. Also, no TMP residues were detected in the plasma of any of the market-ready hogs 24 h after drug administration at either the label dose or twice the label dose. Sulfadoxine residues at concentrations above the maximum residue limit (MRL) of 100 ppb were, however, detected in the plasma, muscle, kidney, liver, and injection sites of hogs slaughtered 1 and 3 d after a single IM administration at the label dose. Although SDX residues were still detectable in the lungs, kidney, liver and plasma of some hogs 10 d after administration of the label dose and twice the label dose, these were below the MRL. Postmortem examination revealed necrosis and inflammation at the injection sites, but no visible deposits of the injected drug.
Topics: Animals; Anti-Infective Agents, Urinary; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Female; Injections, Intramuscular; Kidney; Liver; Lung; Muscle, Skeletal; Sulfadoxine; Sulfanilamides; Swine; Trimethoprim
PubMed: 8904665
DOI: No ID Found -
Poultry Science Dec 1985A pharmacokinetic study of sulfamethoxazole (SMZ) and trimethoprim (TMP) was carried out on Warren hens after intravenous (iv) dosage of 4:1, and oral administration of...
A pharmacokinetic study of sulfamethoxazole (SMZ) and trimethoprim (TMP) was carried out on Warren hens after intravenous (iv) dosage of 4:1, and oral administration of dosages of 5:1, and 2.5:1. The SMZ and TMP half-lives were 8.2 and 2.4 hr, respectively. The ratio between SMZ and TMP serum levels (S/T ratio), after iv administration of the 4:1 dosage, was approximately 20 and remained constant for only 1 hr, while after 5:1 and 2.5:1 oral dosages, the S/T ratio was 40 and 20, respectively, and remained invariable for 12 hr. The oral bioavailability of SMZ and TMP was .46 and .36, respectively. The apparently slower elimination of TMP from serum following oral administration should provide an extended duration of the synergistic antibacterial effect when this route of administration is employed. Finally, the 2.5:1 combination, after oral administration, resulted in an appropriate synergistic ratio (S/T ratio = 20:1) of the drugs in the serum.
Topics: Administration, Oral; Animals; Chickens; Drug Combinations; Female; Half-Life; Kinetics; Sulfamethoxazole; Trimethoprim
PubMed: 4095069
DOI: 10.3382/ps.0642362