Trimethoprim: Prediction of serum concentrations from saliva measurements

Watson, Ian D.; Stewart, Michael J.

doi:10.1007/bf00607960

Cited by 6 publications

(2 citation statements)

References 12 publications

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“…To demonstrate this, Raji cells were sequentially modified with DSPE-PEG 2000 -biotin in vitro and labeled with mSA/Fn3 bispecific CSANs. The CSAN-functionalized Raji cells were then resuspended in culture media supplemented with a clinically relevant concentration of trimethoprim (2 μM; serum concentrations of trimethoprim have been shown to reach peak concentrations of ∼6−15 μM within 2 h of oral dosing 41,42 ) and incubated at 37 °C for up to 2 h. An aliquot of cells was analyzed by flow cytometry at 0, 1, and 2 h. As shown in Figure 5B, the targeting ligands were dissociated from the cell surface in a time-dependent manner, with 95% of the EpCAM-targeted Fn3 domains removed within 2 h. CSANs Direct Reversible Cell−Cell Interactions In Vitro. The ability of CSANs to direct reversible intercellular interactions in vitro was assessed by fluorescence microscopy (Figure 6A−C).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Engineering Reversible Cell–Cell Interactions with Lipid Anchored Prosthetic Receptors

et al. 2018

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Membrane-engineered cells displaying antigen-targeting ligands are useful as both scientific tools and clinical therapeutics. While genetically encoded artificial receptors have proven efficacious, their scope remains limited, as this approach is not amenable to all cell types and the modification is often permanent. Our group has developed a nongenetic method to rapidly, stably, and reversibly modify any cell membrane with a chemically self-assembled nanoring (CSAN) that can function as a prosthetic receptor. Bifunctional CSANs displaying epithelial cell adhesion molecule (EpCAM)-targeted fibronectin domains were installed on the cell membrane through hydrophobic insertion and remained stably bound for ≥72 h in vitro. These CSAN-labeled cells were capable of recognizing EpCAM-expressing target cells, forming intercellular interactions that were subsequently reversed by disassembling the nanoring with the FDA-approved antibiotic, trimethoprim. This study demonstrates the use of this system to engineer cell surfaces with prosthetic receptors capable of directing specific and reversible cell-cell interactions.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Engineering Reversible Cell–Cell Interactions with Lipid Anchored Prosthetic Receptors

et al. 2018

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“…Salivary: serum trimethoprim ratios are 0.87 ± 0.2 (Watson & Stewart 1986); the sinus secretion: serum ratio is 1.33 for trimethoprim and 0.2 for sulphadiazine (Mattila et al 1983). Penetration of co-trimoxazole into breast milk is similar to that into saliva (Arnauld et al 1972), and into aqueous humour is 20% and 30%, respectively, of serum concentrations of trimethoprim and sulphamethoxazole (Salmon et al 1975).…”

Section: Distributionmentioning

confidence: 99%

Clinical Pharmacokinetics of Enzyme Inhibitors in Antimicrobial Chemotherapy

Watson

Stewart

Platt

1988

Clinical Pharmacokinetics

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The effectiveness of some antimicrobial agents can be enhanced by using them in combination; such combinations are termed synergistic. Where one compound potentiates the effect of a second drug they may be coformulated. Inhibition of the bacterial degradation of an active antimicrobial is the basis of clavulanate and sulbactam-potentiated penicillin combinations, and inhibition of degradative pathways in the host is the rationale behind imipenem/cilastatin therapy. Trimethoprim/sulphonamide combinations depend on the maintenance of an effective ratio for synergistic action. In order to achieve potentiation the coformulated drugs should have similar pharmacokinetics. Trimethoprim was originally matched with sulphamethoxazole, since these two drugs have similar elimination half-lives, but the significantly poorer penetration of sulphonamides, their greater non-renal clearance, the emergence of resistance, and the adverse reactions attributable to them argue against the rationale that underlies their coformulation. Time-dependent inhibition of bacterial beta-lactamases by clavulanic acid and sulbactam has extended the use of penicillins which are highly susceptible to beta-lactamase inactivation. The beta-lactamase inhibitors must penetrate to the same extent as the penicillin used with them, and be present long enough to effect inhibition; thus, rapid penetration, similar or slower elimination and equivalent volume of distribution are necessary. These requirements are met for amoxycillin/clavulanic acid, ticarcillin/clavulanic acid and ampicillin/sulbactam combinations. Clavulanic acid is absorbed orally and is given with amoxycillin. However, since sulbactam is labile by this route, the combination of sulbactam with ampicillin to form the prodrug sultamicillin has been necessary to enable an oral form to be developed. Imipenem is metabolised by renal brush-border dehydropeptidases, and may cause proximal tubular necrosis. Cilastatin was designed to inhibit this metabolism, which it effectively does, thereby both potentiating the effect of imipenem and avoiding toxicity. Appropriate matching of the kinetics of coformulated drugs is intended to maximise potentiation and minimise the risk of emergent resistance. The kinetics of the above combinations are discussed in the light of these requirements and the effects of age and disease.

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Respiratory Tract Penetration of Quinolone Antimicrobials: A Case in Study

Ritrovato,

Deeter

1991

Pharmacotherapy

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Antimicrobial lung penetration is thought to be predictive of efficacy in the treatment of lower respiratory tract infections. Lung penetration studies are commonly conducted with new antimicrobial agents to elucidate their potential utility in treating such infections. Although some very useful information may emerge, these studies are complicated by technical difficulties, theoretical assumptions, and numerous intricacies. Many studies describing quinolone penetration into saliva, sputum, bronchial secretions, and lung tissue have been published. In general, quinolone concentrations in lung tissue are 1.5–4 times the serum levels, whereas those in sputum and bronchial secretion are equal to or less than serum, and penetration into saliva is even less. The failure rate predicted from saliva, sputum, and bronchial secretion penetration and marginal in vitro activity of quinolones against streptococci does not consistently correlate with clinical efficacy data. In light of such conflicting data and the high lung tissue penetration of quinolones, the relevance of saliva, sputum, and bronchial secretion studies should be reevaluated. The utility of investigational quinolones in the treatment of lower respiratory tract infections can be determined only by well‐designed clinical trials.

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Trimethoprim: Prediction of serum concentrations from saliva measurements

Cited by 6 publications

References 12 publications

Engineering Reversible Cell–Cell Interactions with Lipid Anchored Prosthetic Receptors

Engineering Reversible Cell–Cell Interactions with Lipid Anchored Prosthetic Receptors

Clinical Pharmacokinetics of Enzyme Inhibitors in Antimicrobial Chemotherapy

Respiratory Tract Penetration of Quinolone Antimicrobials: A Case in Study

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