Population Pharmacokinetic Modelling of Orally Administered Doxycycline to Rabbits at Different Ages

Mileva, Rositsa; Rusenov, Anton; Milanova, Aneliya

doi:10.3390/antibiotics10030310

Cited by 4 publications

(5 citation statements)

References 28 publications

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“…MMPs are the only known enzymes that can degrade these components. MMP-1, along with MMP-2, -3, -9, -13, and -14, belongs in this group [9,[32][33][34][35]. MTB upregulates MMP-1, -2, -8, and -9, with MMP-1 acting as the main collagenase in TB immunopathology.…”

Section: Discussionmentioning

confidence: 99%

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Doxycycline as a Potential MMP‐1 Inhibitor for the Treatment of Spondylitis Tuberculosis: A Study in Rabbit Model

Siregar

Lelo

Rahyussalim

et al. 2023

BioMed Research International

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Background. Tuberculosis (TB) of the spine is a highly disruptive disease, especially in underdeveloped and developing countries. This condition requires standard TB treatment for 9–18 months, which increases patient risk of drug-resistant TB. Consequently, this raises the concern of adopting additional therapies to shorten the treatment duration, improve the efficacy of anti-TB drugs, and further decrease damage in the affected tissues and organs. Matrix metalloproteinase- (MMP-) 1 is a key regulator of the destruction of the extracellular matrix and associated proteins and is a new potential target for TB treatment research. In the present study, we investigated the effects of doxycycline as an MMP-1 inhibitor in patients with spondylitis TB. Methods. Seventy-two New Zealand white rabbits with spondylitis TB were divided into 12 different groups based on incubation period (2, 4, 6, and 8 weeks) and doxycycline administration (without, 1 mg/kg body weight (BW), and 5 mg/kg BW). We observed the course of infection through the blood concentration changes and immunohistochemical examination of MMP-1, in addition to BTA staining, culture, polymerase chain reaction (PCR), and histopathological examination. Results. Treatment with once daily 5 mg/kg BW doxycycline significantly improved the blood MMP-1 level ( p < 0.05 ) compared with the placebo and 1 mg/kg BW doxycycline. A significantly reduced ongoing infection and a higher healing rate were demonstrated in rabbits with a higher doxycycline dose through BTA staining, culture, PCR, and histopathology. Various degrees of vertebral endplates, vertebral body, and intervertebral disc destruction were observed in 32 rabbits with positive histopathological findings, in addition to positive inflammatory cell infiltration, characterized by numerous lymphocytes, macrophages, and epithelial cells, as well as abundant granulation tissue and necrotic substances proximal to the inoculated vertebral area. Bone and intervertebral disc destructions were more apparent in the untreated rabbits. Conclusion. Our study demonstrated the potential of doxycycline as an adjunctive treatment in spondylitis TB. However, limitations remain regarding the differences in the pathogenesis and virulence of Mycobacterium tuberculosis between rabbit and human systems, sample size, and the dose-dependent effect of doxycycline. Further studies are needed to address these issues.

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Section: Discussionmentioning

confidence: 99%

“…Inoculated rabbits were given doxycycline for 4 weeks following the designated incubation periods, during which the animals were placed in individual cages in one large room. In addition, rabbits in the control groups (groups A, D, G, and J) received 3 mL saline orally [34][35][36].…”

Section: Experimental Design Using a Randomization Table Mtbmentioning

confidence: 99%

Doxycycline as a Potential MMP‐1 Inhibitor for the Treatment of Spondylitis Tuberculosis: A Study in Rabbit Model

Siregar

Lelo

Rahyussalim

et al. 2023

BioMed Research International

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“…However, there was no significant difference noted in stiffness or stress at failure at all three time points. Despite its effectiveness, various adverse effects (e.g., gastritis, esophageal erosion, heartburn, nausea, or vomiting) have been reported [ 51 ] after long-term systemic use of doxycycline.…”

Section: Discussionmentioning

confidence: 99%

“…The blood sample was freshly centrifuged at 2500 rpm for 15 min so as to separate plasma from whole blood. The drug levels of doxycycline in the tissue and plasma were evaluated using Hitachi L-2200R high-performance liquid chromatography (Tokyo, Japan) [ 50 , 51 ]. The mobile phase contained acetonitrile, distilled water, and phosphoric acid (pH = 2.5) (50/20/30, v / v / v ).…”

Section: Methodsmentioning

confidence: 99%

Electrospun, Resorbable, Drug-Eluting, Nanofibrous Membranes Promote Healing of Allograft Tendons

Weng

Hsu

et al. 2022

Membranes

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In spite of advances in medical technology, the repair of Achilles tendon ruptures remains challenging. Reconstruction with an autograft tendon provides the advantage of a higher healing rate; nevertheless, the development of donor-site morbidity cannot be ignored. We developed biodegradable, drug-eluting, nanofibrous membranes employing an electrospinning technique and evaluated their effectiveness on the healing of allograft tendons. Poly-D-L-lactide-glycolide was used as the polymeric material for the nanofibers, while doxycycline was selected as the drug for delivery. The in vitro and in vivo drug-release profiles were investigated. The biomechanical properties of allografted Achilles tendons repaired using the nanofibrous membranes were tested in euthanized rabbits at 2-, 4-, and 6-week time intervals. Histological examination was performed for the evaluation of tissue reaction and tendon healing. The level of postoperative animal activity was also monitored using an animal behavior cage. The experimental results showed that the degradable nanofibers used as a vehicle could provide sustained release of doxycycline for 42 days after surgery with very low systemic drug concentration. Allograft Achilles tendon reconstruction assisted by drug-loaded nanofibers was associated with better biomechanical properties at 6 weeks post-surgery. In addition, the animals exhibited a better level of activity after surgery. The use of drug-eluting, nanofibrous membranes could enhance healing in Achilles tendon allograft reconstruction surgery.

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“…Population pharmacokinetics is an effective means of expalining the random effects of drugs on subjects [ 16 , 17 ]. It encompasses inter-individual and intra-individual/inter-experiment random variations, which can solve the problem that small animal such as fish cannot be continuously sampled [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetics of Difloxacin in Crucian Carp (Carassius auratus) after a Single Oral Administration

Zhang

Chen

et al. 2023

Veterinary Sciences

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This study aimed to investigate the population pharmacokinetics of difloxacin in crucian carp (Carassius auratus) orally provided a single dose of 20 mg/kg body weight (BW). To achieve this, fish were sampled at various intervals using a sparse sampling strategy, and plasma samples were analyzed using the high-performance liquid chromatography (HPLC) method. Subsequently, naïve average data were analyzed using a non-compartmental method, and a population model was developed based on the nonlinear mixed effects approach. The covariate of BW and the relationship between covariances were sequentially incorporated into the population model. However, it was found that only covariance and not BW affected the population parameters. Therefore, the covariance model was taken as the final population model, which revealed that the typical values of the absorption rate constant (tvKa), apparent volume of distribution per bioavailability (tvV), and clearance rate per bioavailability (tvCl) were 1.18 1/h, 14.18 L/kg, and 0.20 L/h/kg, respectively. Based on the calculated free AUC/MIC values, the current oral dose of difloxacin (20 mg/kg BW) cannot generate adequate plasma concentrations to inhibit pathogens with MIC values above 0.83 μg/mL. Further study should be carried out to collect the pathogens from crucian carp and determine the MIC data of difloxacin against them. Pharmacodynamic experiments must also be further carried out to determine the optimal therapeutic dose for the treatment of Aeromonas hydrophila infection.

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Population Pharmacokinetic Modelling of Orally Administered Doxycycline to Rabbits at Different Ages

Cited by 4 publications

References 28 publications

Doxycycline as a Potential MMP‐1 Inhibitor for the Treatment of Spondylitis Tuberculosis: A Study in Rabbit Model

Doxycycline as a Potential MMP‐1 Inhibitor for the Treatment of Spondylitis Tuberculosis: A Study in Rabbit Model

Electrospun, Resorbable, Drug-Eluting, Nanofibrous Membranes Promote Healing of Allograft Tendons

Population Pharmacokinetics of Difloxacin in Crucian Carp (Carassius auratus) after a Single Oral Administration

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