Enoxacin
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Enoxacin is a second-generation fluoroquinolone. It has the chemical formula l-ethyl-6-fluoro-I, 4-dihydro-4-oxo-7 piperazinyl)-I, 8-naphthyridine-3-carboxylic acid (see Figure 112.1). Overall, the in vitro activity of enoxacin is comparable with that of norfloxacin or lomefloxacin (see Chapter 102, Norfloxacin, and Chapter 116, Lomefloxacin) but inferior to those of other fluoroquinolones, such as ciprofloxacin (see Chapter 101, Ciprofloxacin) and moxifloxacin (Bauernfeind and Ullmann, 1984; Chin and Neu, 1983; Guimaraes and Noone, 1986; Henwood and Monk, 1988; Ismaeel and Tayeb, 1993; Reeves et al., 1984; Siporin and Towse, 1984; Weinstein, 1988; see Chapter 105, Moxifloxacin).
Pharmacokinetic/Pharmacodynamic Modeling of Antibiotics
Hartmut Derendorf, Günther Hochhaus in Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Blaser, Zinner, and colleagues30–34 worked extensively with an interesting model. The model is designed to expose bacteria to changing drug concentrations according to two-compartment pharmacokinetics (Figure 11). The central compartment consists of tubing, the lumina of the capillaries within the capillary units, and a graduated central reservoir with magnetic stirrer. Antibiotic-containing broth is pumped from the central reservoir by a peristaltic pump at a specified flow rate through the tubing. Capillary units allow for a large interface between the peripheral and central compartments. Each unit consists of a polycarbonate tube through which runs a bundle of 150 artificial capillaries. The walls of these fibers selectively allowed passage of small molecules of less than 10,000 Da. Antibiotics easily pass through while bacteria are retained. Drugs are administered by injection into the central compartment. Good agreement could be achieved between concentration-time profiles produced by the model and human data (in skin blister fluid). Figure 12 shows the bactericidal activity of different dosing regimens of enoxacin. Rapid and profound bacterial killing of susceptible strains occurred following the initial dose of enoxacin. The initial bactericidal effects increased with increasing ratios of peak concentrations to MIC. In contrast to the bactericidal effect of the initial dose, little or no effect is observed following the second and third dose against regrowing strains. The authors further investigated the relationship between the difference in bacterial counts and ratio of peak concentrations to MIC value. The once-a-day dosing regimen provided a better killing of P. aeruginosa than did the every-4-h dosing regimen due to the higher peak concentrations with the once-a-day dosing regimen. The authors concluded that a less frequent dosing is more effective and that peak concentration/MIC values can be used as indicators of antibacterial potency in their model.
Emerging therapeutic targets for osteoporosis
Published in Expert Opinion on Therapeutic Targets, 2020
Luigi Gennari, Daniela Merlotti, Alberto Falchetti, Cristina Eller Vainicher, Roberta Cosso, Iacopo Chiodini
The suppression of bone resorption by targeting the vacuolar H+-ATPases (V-ATPases) of the OC ruffled border might represent an alternative approach for the development of novel antiresorptive compounds. In fact, V-ATPases are essential for the acidification of resorption lacunae, mobilizing bone mineral content and allowing CK and other proteases to digest bone matrix proteins. However, since V-ATPases are ubiquitous proton pumps, there is the necessity to identify selective mechanisms directly targeting V-ATPases within the OC ruffled border, without affecting those that are required for everyday cell survival in other tissues. Some compounds targeting ruffled border V-ATPases as well as their OC-specific regulation or trafficking have been identified, but so far none of them has been translated to the clinic [63,64]. Enoxacin is a fluoroquinolone that is able to prevent V-ATPase insertion into the ruffled-border membrane, with potential advantages in terms of clinical development [64]. However, a long-term treatment with this agent (due to its antibiotic activity) might induce dysbacteriosis and gastrointestinal discomfort. Thus, a BP derivative of enoxacin (Bis-enoxacin) has been more recently developed, which targets more specifically the skeleton. In a preclinical study in ovariectomized (OVX) mice, bis-enoxacin prevented bone loss and improved the bone biomechanical properties better than zoledronate [65].
Emerging clinical investigational drugs for the treatment of amyotrophic lateral sclerosis
Published in Expert Opinion on Investigational Drugs, 2023
Loreto Martinez-Gonzalez, Ana Martinez
(NCT04840823) is an oral bactericidal fluoroquinolone agent present in the clinical setting for more than20 years that has been reported as the first small-molecule enhancer of microRNA (miRNA) maturation by increasing the activity of the key endoribonuclease DICER, essential for this process [24]. Downregulation of miRNA levels is a common molecular feature of ALS subjects [25]. Treatment with enoxacin improved miRNA maturation, mRNA metabolism and therefore protein homeostasis in ALS cellular models including the SOD1G93A mice [26]. On March 2015, enoxacin received an orphan designation by the EMA (EU/3/15/1459) for ALS treatment [27]. Currently, the trial REALS (Repurposed Enoxacion for the treatment of patients with ALS) will assess the safety of the drug enoxacin at specific dose levels in 36 adults with ALS.
In vivo activity and atom pair fingerprint analysis of MMV665941 against the apicomplexan parasite Babesia microti, the causative agent of babesiosis in humans and rodents
Published in Pathogens and Global Health, 2023
Mohamed Abdo Rizk, Shimaa Abd El-Salam El-Sayed, Ikuo Igarashi
Treatment of B. microti–infected mice with MMV665941 at a dose rate of 5 mg/kg exhibited significant inhibition (P < 0.05) of the emitted fluorescence signals from days 4 to 12 post-inoculation (p.i.) in comparison with control mice (Figure 1(a)). MMV665941 administered orally at a dose rate of 5 mg/kg caused 62.10%, 49.88%, and 74.23% inhibitions in parasite growth at days 4, 6, and 8 p.i., respectively (Figure 1(a)). These results are higher than the 21% inhibition for 100 mg/kg subcutaneous injections of enoxacin, 15% for 150 mg/kg subcutaneous injections of norfloxacin, 23% for 700 mg/kg subcutaneous injections of ofloxacin [4], 48.54% for 25 mg/kg intraperitoneal injections of MMV667488, 45.60% for 25 mg/kg intraperitoneal injections of MMV007285, and 40.40% for 25 mg/kg intraperitoneal injections of MMV019881 [30], and 58.3% for 30 mg/kg subcutaneous injections of allicin [31], respectively. The in vivo inhibitory effect of MMV665941 was nearly similar to 77.5% inhibition for 500 mg/kg intraperitoneal injections of thiostrepton, 68.5% for 500 mg/kg intraperitoneal injections of clindamycin [32]. Such finding confirms the potential antibabesial efficacy of single-low dose from MMV665941 over the other recently identified antibabesial drugs.
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