Comparison of the In Vitro Tolerance and In Vivo Efficacy of Traditional Timolol Maleate Eye Drops versus New Formulations with Bioadhesive Polymers

AbstractTo be effective, chemotherapy against tuberculosis (TB) must kill the intracellular population of the pathogen, Mycobacterium tuberculosis. However, how host cell microenvironments affect antibiotic accumulation and efficacy remains unclear. Here, we use correlative light, electron, and ion microscopy to investigate how various microenvironments within human macrophages affect the activity of pyrazinamide (PZA), a key antibiotic against TB. We show that PZA accumulates heterogeneously among individual bacteria in multiple host cell environments. Crucially, PZA accumulation and efficacy is maximal within acidified phagosomes. Bedaquiline, another antibiotic commonly used in combined TB therapy, enhances PZA accumulation via a host cell-mediated mechanism. Thus, intracellular localisation and specific microenvironments affect PZA accumulation and efficacy. Our results may explain the potent in vivo efficacy of PZA, compared to its modest in vitro activity, and its critical contribution to TB combination chemotherapy.

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Kynurenic Acid Accelerates Healing of Corneal Epithelium In Vitro and In Vivo

Pharmaceuticals ◽

10.3390/ph14080753 ◽

2021 ◽

Vol 14 (8) ◽

pp. 753

Author(s):

Anna Matysik-Woźniak ◽

Waldemar A. Turski ◽

Monika Turska ◽

Roman Paduch ◽

Mirosław Łańcut ◽

...

Keyword(s):

Epithelial Cell ◽

Corneal Epithelium ◽

Kynurenic Acid ◽

Pharmaceutical Products ◽

Corneal Epithelial Cell ◽

Eye Drops ◽

Conjunctival Epithelium ◽

Corneal Erosion

Kynurenic acid (KYNA) is an endogenous compound with a multidirectional effect. It possesses antiapoptotic, anti-inflammatory, and antioxidative properties that may be beneficial in the treatment of corneal injuries. Moreover, KYNA has been used successfully to improve the healing outcome of skin wounds. The aim of the present study is to evaluate the effects of KYNA on corneal and conjunctival cells in vitro and the re-epithelization of corneal erosion in rabbits in vivo. Normal human corneal epithelial cell (10.014 pRSV-T) and conjunctival epithelial cell (HC0597) lines were used. Cellular metabolism, cell viability, transwell migration, and the secretion of IL-1β, IL-6, and IL-10 were determined. In rabbits, after corneal de-epithelization, eye drops containing 0.002% and 1% KYNA were applied five times a day until full recovery. KYNA decreased metabolism but did not affect the proliferation of the corneal epithelium. It decreased both the metabolism and proliferation of conjunctival epithelium. KYNA enhanced the migration of corneal but not conjunctival epithelial cells. KYNA reduced the secretion of IL-1β and IL-6 from the corneal epithelium, leaving IL-10 secretion unaffected. The release of all studied cytokines from the conjunctival epithelium exposed to KYNA was unchanged. KYNA at higher concentration accelerated the healing of the corneal epithelium. These favorable properties of KYNA suggest that KYNA containing topical pharmaceutical products can be used in the treatment of ocular surface diseases.

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P074 In vitro and in vivo efficacy of linezolid on Treponema pallidum, the syphilis agent

10.1136/sextrans-2021-sti.208 ◽

2021 ◽

Author(s):

L Giacani ◽

A Haynes ◽

M Vall Mayans ◽

M Ubals Cazorla ◽

C Nieto ◽

...

Keyword(s):

Treponema Pallidum ◽

In Vivo Efficacy

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The Use of an Opacitometer to Compare the In Vitro Cornea Opacifying Effects of Timolol With and Without Benzalkonium Chloride

Alternatives to Laboratory Animals ◽

10.1177/026119299101900220 ◽

1991 ◽

Vol 19 (2) ◽

pp. 263-270

Author(s):

Haruyoshi Igarashi ◽

Yasunaga Katsuta ◽

Yoshiharu Nakazato ◽

Tohru Kawasaki

Keyword(s):

Benzalkonium Chloride ◽

Additive Effects ◽

Timolol Maleate ◽

Epithelial Surface ◽

Endothelial Surface ◽

Draize Test ◽

Corneal Opacities

We have evaluated a new in vitro opacitometer method as an alternative to the in vivo Draize test for ocular irritancy. Several concentrations of timolol maleate (timolol) with or without 0.005% benzalkonium chloride were applied to porcine isolated corneas which were either intact or with the epithelium, endothelium, or both epithelium and endothelium removed. Corneal opacities were measured using an opacitometer. In general, timolol with benzalkonium chloride caused a greater degree of opacity to develop in the cornea than did timolol alone. At the lower concentrations of timolol, the increased opacity probably represented additive effects of the two compounds. However, at the highest concentration of timolol (5 x 10 2M), there was an enhanced opacification in the presence of benzalkonium chloride, which may have been due to an increase in penetration, particularly through the epithelium. Timolol caused a greater degree of opacity to develop in the isolated intact porcine corneas when the drug was applied to the endothelial surface, than when applied to the epithelial surface or to both the epithelial and endothelial surfaces. However, timolol with benzalkonium chloride caused a greater degree of opacity in the intact cornea, when the drug was applied to both surfaces than when it was applied only to the epithelial or the endothelial surface.

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Efficacy of a novel lantibiotic, CMB001, against MRSA

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkab040 ◽

2021 ◽

Author(s):

Jerzy Karczewski ◽

Christine M Brown ◽

Yukari Maezato ◽

Stephen P Krasucki ◽

Stephen J Streatfield

Keyword(s):

Antibacterial Activity ◽

Pharmacokinetic Analysis ◽

Maximum Tolerable Dose ◽

In Vivo Efficacy ◽

Clostridioides Difficile ◽

Alternative Treatment Option ◽

Significant Damage ◽

Tolerable Dose

Abstract Objectives To evaluate the efficacy of a novel lantibiotic, CMB001, against MRSA biofilms in vitro and in an in vivo experimental model of bacterial infection. Methods Antibacterial activity of CMB001 was measured in vitro after its exposure to whole blood or to platelet-poor plasma. In vitro efficacy of CMB001 against a Staphylococcus aureus biofilm was studied using scanning electron microscopy. The maximum tolerable dose in mice was determined and a preliminary pharmacokinetic analysis for CMB001 was performed in mice. In vivo efficacy was evaluated in a neutropenic mouse thigh model of infection. Results CMB001 maintained its antibacterial activity in the presence of blood or plasma for up to 24 h at 37°C. CMB001 efficiently killed S. aureus within the biofilm by causing significant damage to the bacterial cell wall. The maximum tolerable dose in mice was established to be 10 mg/kg and could be increased to 30 mg/kg in mice pretreated with antihistamines. In neutropenic mice infected with MRSA, treatment with CMB001 reduced the bacterial burden with an efficacy equivalent to that of vancomycin. Conclusions CMB001 offers potential as an alternative treatment option to combat MRSA. It will be of interest to evaluate the in vivo efficacy of CMB001 against infections caused by other pathogens, including Clostridioides difficile and Acinetobacter baumannii, and to expand its pharmacokinetic/pharmacodynamic parameters and safety profile.

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Ophthalmic Drug Dosage Forms: Characterisation and Research Methods

The Scientific World JOURNAL ◽

10.1155/2014/861904 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 87

Author(s):

Przemysław Baranowski ◽

Bożena Karolewicz ◽

Maciej Gajda ◽

Janusz Pluta

Keyword(s):

Defense Mechanisms ◽

Drug Application ◽

Drug Dosage ◽

Eye Drops ◽

Eye Tissues ◽

Ophthalmic Drug ◽

Application Frequency

This paper describes hitherto developed drug forms for topical ocular administration, that is, eye drops, ointments,in situgels, inserts, multicompartment drug delivery systems, and ophthalmic drug forms with bioadhesive properties. Heretofore, many studies have demonstrated that new and more complex ophthalmic drug forms exhibit advantage over traditional ones and are able to increase the bioavailability of the active substance by, among others, reducing the susceptibility of drug forms to defense mechanisms of the human eye, extending contact time of drug with the cornea, increasing the penetration through the complex anatomical structure of the eye, and providing controlled release of drugs into the eye tissues, which allows reducing the drug application frequency. The rest of the paper describes recommendedin vitroandin vivostudies to be performed for various ophthalmic drugs forms in order to assess whether the form is acceptable from the perspective of desired properties and patient’s compliance.

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