scholarly journals Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 1. THR-149

2021 ◽  
Author(s):  
Marc Vanhove ◽  
Bernard Noppen ◽  
Jean-Marc Wagner ◽  
Tine Van Bergen ◽  
Philippe Barbeaux ◽  
...  
Keyword(s):  
Pharmacokinetic Model ◽  
Systemic Exposure ◽  
Mathematical Expression ◽  
Secondary Complications ◽  
Pharmacological Agents ◽  
Rabbit Eye ◽  
High Concentrations ◽  
Circulating Levels ◽  
Pharmacokinetic Approach ◽  
Systemic Compartment

AbstractIntravitreal (IVT) injection of pharmacological agents is an established and widely used procedure for the treatment of many posterior segment of the eye diseases. IVT injections permit drugs to reach high concentrations in the retina whilst limiting systemic exposure. Beyond the risk of secondary complications such as intraocular infection, the potential of systemic adverse events cannot be neglected. Therefore, a detailed understanding of the rules governing systemic exposure following IVT drug administration remains a prerequisite for the evaluation and development of new pharmacological agents intended for eye delivery. We present here a novel mathematical model to describe and predict circulating drug levels following IVT in the rabbit eye, a species which is widely used for drug delivery, pharmacokinetic, and pharmacodynamic studies. The mathematical expression was derived from a pharmacokinetic model that assumes the existence of a compartment between the vitreous humor compartment itself and the systemic compartment. We show that the model accurately describes circulating levels of THR-149, a plasma kallikrein inhibitor in development for the treatment of diabetic macular edema. We hypothesize that the model based on the rabbit eye has broader relevance to the human eye and can be used to analyze systemic exposure of a variety of drugs delivered in the eye.

scholarly journals Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687

2021 ◽  
Author(s):  
Marc Vanhove ◽  
Jean-Marc Wagner ◽  
Bernard Noppen ◽  
Bart Jonckx ◽  
Elke Vermassen ◽  
...  
Keyword(s):  
General Circulation ◽  
Pharmacokinetic Model ◽  
Systemic Exposure ◽  
Age Related Macular Degeneration ◽  
Whole Body ◽  
Pharmacological Agents ◽  
Age Related ◽  
Pharmacokinetic Properties ◽  
High Concentrations ◽  
Systemic Compartment

AbstractIntravitreal (IVT) injection remains the preferred administration route of pharmacological agents intended for the treatment of back of the eye diseases such as diabetic macular edema (DME) and neovascular age-related macular degeneration (nvAMD). The procedure enables drugs to be delivered locally at high concentrations whilst limiting whole body exposure and associated risk of systemic adverse events. Nevertheless, intravitreally-delivered drugs do enter the general circulation and achieving an accurate understanding of systemic exposure is pivotal for the evaluation and development of drugs administered in the eye. We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that represent the pharmacokinetic model, thereby allowing data analysis with standard nonlinear regression analysis. The model accurately describes circulating levels of THR-687 following IVT administration in relevant animal models, and we suggest that this approach is relevant to a range of drugs and analysis of subsequent systemic exposure.

Application of the EYTEX™ System to the Evaluation of Cosmetic Products and their Ingredients

1992 ◽  
Vol 20 (1) ◽  
pp. 146-163
Author(s):  
Francis H. Kruszewski ◽  
Laura H. Hearn ◽  
Kyle T. Smith ◽  
Janice J. Teal ◽  
Virginia C. Gordon ◽  
...  
Keyword(s):  
Double Blind ◽  
Eye Irritation ◽  
Ocular Irritation ◽  
Rabbit Eye ◽  
Wide Range ◽  
High Concentrations ◽  
Alkaline Membrane ◽  
Positive Agreement

465 cosmetic product formulations and raw ingredients were evaluated with the EYTEX™ system to determine the potential of this in vitro alternative for identifying eye irritation potential. The EYTEX™ system is a non-animal, biochemical procedure developed by Ropak Laboratories, Irvine, CA, that was designed to approximate the Draize rabbit eye irritation assay for the evaluation of ocular irritation. Avon Products Inc. provided all the test samples, which included over 30 different product types and represented a wide range of eye irritancy. All the EYTEX™ protocols available at the time of this study were used. Samples were evaluated double-blind with both the membrane partition assay (MPA) and the rapid membrane assay (RMA). When appropriate, the standard assay (STD) and the alkaline membrane assay (AMA) were used, as well as specific, documented protocol modifications. EYTEX™ results were correlated with rabbit eye irritation data which was obtained from the historical records of Avon Products Inc. A positive agreement of EYTEX™ results with the in vivo assay was demonstrated by an overall concordance of 80%. The assay error was 20%, of which 18% was due to an overestimation of sample irritancy (false positives) and 2% was attributed to underestimation (false negatives). Overestimation error in this study was due in part to the inability of the protocols to accurately classify test samples with very low irritation potential. Underestimation of sample irritancy was generally associated with ethoxylated materials and high concentrations of specific types of surfactants. 100% sensitivity and 85% predictability were described by the data, indicating the efficiency of EYTEX™ in identifying known irritants. A specificity rate of 39% showed the EYTEX™ assay to be weak in discerning non-irritants. However, the EYTEX™ protocols used in this study were not designed to identify non-irritants. A compatibility rate of 99% proved the effectiveness of the EYTEX™ assay in accommodating a diversity of product types. The EYTEX™ system protocols, when used appropriately, can provide a conservative means of assessing the irritant potential of most cosmetic formulations and their ingredients.

scholarly journals Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 349
Author(s):  
Sepideh Mirzaei ◽  
Ali Zarrabi ◽  
Farid Hashemi ◽  
Amirhossein Zabolian ◽  
Hossein Saleki ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Adverse Effects ◽  
Cancer Progression ◽  
Related Factor ◽  
Pharmacological Agents ◽  
Nrf2 Signaling Pathway ◽  
High Concentrations ◽  
Genetic Interventions ◽  
Underlying Mechanisms ◽  
In Cells

Doxorubicin (DOX) is extensively applied in cancer therapy due to its efficacy in suppressing cancer progression and inducing apoptosis. After its discovery, this chemotherapeutic agent has been frequently used for cancer therapy, leading to chemoresistance. Due to dose-dependent toxicity, high concentrations of DOX cannot be administered to cancer patients. Therefore, experiments have been directed towards revealing underlying mechanisms responsible for DOX resistance and ameliorating its adverse effects. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is activated to increase levels of reactive oxygen species (ROS) in cells to protect them against oxidative stress. It has been reported that Nrf2 activation is associated with drug resistance. In cells exposed to DOX, stimulation of Nrf2 signaling protects cells against cell death. Various upstream mediators regulate Nrf2 in DOX resistance. Strategies, both pharmacological and genetic interventions, have been applied for reversing DOX resistance. However, Nrf2 induction is of importance for alleviating side effects of DOX. Pharmacological agents with naturally occurring compounds as the most common have been used for inducing Nrf2 signaling in DOX amelioration. Furthermore, signaling networks in which Nrf2 is a key player for protection against DOX adverse effects have been revealed and are discussed in the current review.

scholarly journals The Effect of Bacterial Endotoxin LPS on Serotonergic Modulation of Glutamatergic Synaptic Transmission

Biology ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 210
Author(s):  
Jate Bernard ◽  
Abigail Greenhalgh ◽  
Oscar Istas ◽  
Nicole T. Marguerite ◽  
Robin L. Cooper
Keyword(s):  
Synaptic Transmission ◽  
Motor Neurons ◽  
Positive Outcome ◽  
The Body ◽  
Receptor Subtype ◽  
Pharmacological Agents ◽  
Enhanced Transmission ◽  
Glutamatergic Synaptic Transmission ◽  
The Central Nervous System ◽  
High Concentrations

The release of the endotoxin lipopolysaccharides (LPS) from gram-negative bacteria is key in the induction of the downstream cytokine release from cells targeting cells throughout the body. However, LPS itself has direct effects on cellular activity and can alter synaptic transmission. Animals experiencing septicemia are generally in a critical state and are often treated with various pharmacological agents. Since antidepressants related to the serotonergic system have been shown to have a positive outcome for septicemic conditions impacting the central nervous system, the actions of serotonin (5-HT) on neurons also exposed to LPS were investigated. At the model glutamatergic synapse of the crayfish neuromuscular junction (NMJ), 5-HT primarily acts through a 5-HT2A receptor subtype to enhance transmission to the motor neurons. LPS from Serratia marcescens also enhances transmission at the crayfish NMJ but by a currently unknown mechanism. LPS at 100 µg/mL had no significant effect on transmission or on altering the response to 5-HT. LPS at 500 µg/mL increased the amplitude of the evoked synaptic excitatory junction potential, and 5-HT in combination with 500 µg/mL LPS continued to promote enhanced transmission. The preparations maintained responsiveness to serotonin in the presence of low or high concentrations of LPS.

scholarly journals Polyethylene glycol 400 (PEG400) affects the systemic exposure of oral drugs based on multiple mechanisms: taking berberine as an example

RSC Advances ◽  
2017 ◽  
Vol 7 (5) ◽  
pp. 2435-2442 ◽  
Author(s):  
Bing-Liang Ma ◽  
Yan Yang ◽  
Yan Dai ◽  
Qiao Li ◽  
Ge Lin ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Systemic Exposure ◽  
Lymphatic Transport ◽  
Oral Drugs ◽  
Polyethylene Glycol 400 ◽  
High Concentrations

High concentrations of PEG400 increase in vivo exposure to berberine (D) by increasing its solubility (A), permeability (B), and lymphatic transport (C).

scholarly journals Sacubitril/valsartan (LCZ696) Significantly Reduces Aldosterone and Increases cGMP Circulating Levels in a Canine Model of RAAS Activation

2018 ◽  
Author(s):  
Jonathan P Mochel ◽  
Chi Hse Teng ◽  
Mathieu Peyrou ◽  
Jerome Giraudel ◽  
Meindert Danhof ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systemic Exposure ◽  
Plasma Renin ◽  
Canine Model ◽  
Angiotensin Receptors ◽  
Angiotensin I ◽  
Once Daily ◽  
Salt Diet ◽  
Low Salt ◽  
Circulating Levels

AbstractSimultaneous blockade of angiotensin receptors and enhancement of natriuretic peptides (NP) by the first-in-class angiotensin receptor neprilysin (NEP) inhibitor sacubitril/valsartan constitutes an effective approach to treating heart failure. This study examined the effects of sacubitril/valsartan (225 and 675mg/day) vs. placebo, sacubitril (360mg/day), valsartan (900mg/day), and benazepril (5mg/day) on the dynamics of the renin-angiotensin-aldosterone system (RAAS) and the NP system in dogs. Beagle dogs (n=18) were fed a low-salt diet (0.05% Na) for 15 days to model RAAS activation observed in clinical heart failure. Drugs were administered once daily during the last 10 days, while the effects on the RAAS and NPs were assessed on days 1, 5, and 10. Steady-state pharmacokinetics of the test agents were evaluated on day 5. Compared with placebo, sacubitril/valsartan (675mg) substantially increased cGMP circulating levels, while benazepril and valsartan showed no effect. Additionally, sacubitril/valsartan (675mg) and valsartan significantly increased plasma renin activity, angiotensin I and angiotensin II concentrations. Finally, sacubitril/valsartan (both doses), and valsartan significantly decreased plasma aldosterone vs. placebo. Systemic exposure to valsartan following sacubitril/valsartan 675mg administration was similar to that observed with valsartan 900mg administration alone. Sacubitril/valsartan favorably modulates the dynamics of the renin and NP cascades through complementary NEP and RAAS inhibition.

scholarly journals Release of Transgenic Human Insulin from Gastric G Cells: A Novel Approach for the Amelioration of Diabetes

Endocrinology ◽  
2005 ◽  
Vol 146 (6) ◽  
pp. 2610-2619 ◽  
Author(s):  
Yu-Chun Lu ◽  
Catia Sternini ◽  
Enrique Rozengurt ◽  
Elena Zhukova
Keyword(s):  
Gene Therapy ◽  
Blood Glucose ◽  
Human Insulin ◽  
Control Release ◽  
Diabetic Patients ◽  
Intragastric Administration ◽  
Pharmacological Agents ◽  
G Cells ◽  
G Cell ◽  
Circulating Levels

Abstract We explored the hypothesis that meal-regulated release of insulin from gastric G cells can be used for gene therapy for diabetes. We generated transgenic mice in which the coding sequence of human insulin has been knocked into the mouse gastrin gene. Insulin was localized specifically to antral G cells of G-InsKi mice by double immunofluorescence staining using antibodies against insulin and gastrin. Insulin extracted from antral stomach of G-InsKi mice decreased blood glucose upon injection into streptozotocin-diabetic mice. Intragastric administration of peptone, a known potent luminal stimulant of gastrin secretion, induced an increase in circulating levels of transgenic human insulin from 10.7 ± 2 to 23.3 ± 4 pm in G-InsKi mice. Although G cell-produced insulin decreased blood glucose in G-InsKi mice, it did not cause toxic hypoglycemia. Proton pump inhibitors, pharmacological agents that increase gastrin output, caused a further increase in the circulating levels of gastric insulin (41.5 ± 2 pm). G cell-produced insulin was released into circulation in response to the same meal-associated stimuli that control release of gastrin. The most striking aspect of the results presented here is that in the presence of the G-InsKi allele, Ins2Akita/+ mice exhibited a marked prolongation of life span. These results imply that G cell-derived transgenic insulin is beneficial in the amelioration of diabetes. We suggest that an efficient G cells-based insulin gene therapy can relieve diabetic patients from daily insulin injections and protect them from complications of insulin insufficiency while avoiding episodes of toxic hypoglycemia.

scholarly journals Evaluation of toxicity after periocular and intravitreal administration of carboplatin in rabbit eyes

2011 ◽  
Vol 80 (4) ◽  
pp. 385-390 ◽  
Author(s):  
Denisa Darsová ◽  
Pavel Pochop ◽  
Luděk Vajner ◽  
Daniela Kodetová ◽  
Jiří Uhlík ◽  
...  
Keyword(s):  
Intravitreal Injection ◽  
White Male ◽  
Systemic Exposure ◽  
Histopathologic Examination ◽  
Anatomical Structures ◽  
Group Iii ◽  
Rabbit Eye ◽  
Group I ◽  
Group Ii ◽  
Dose Limiting Toxicity

The aim of this study was to characterize the extent of toxicity of focal carboplatin administration and to identify the dose limiting toxicity in rabbit eyes depending on administered concentrations. New Zealand white male rabbits (n = 18) were treated with 1 of 3 regimens: a single periocular injection of 15 mg of carboplatin (group I), a single periocular injection of 30 mg of carboplatin (group II) and a single transcorneal intravitreal injection of 0.05 mg of carboplatin (group III). Ophthalmologic examinations and vitreous samplings were performed under dissociative anaesthesia at regular intervals during next 2 (groups I and III) or 3 (group II) weeks. Carboplatin concentrations in vitreous samples were assessed by atomic absorption spectroscopy. At the end of experiments, all rabbit eyes were obtained for histopathologic examination. Clinical and histological evidence of toxicity was graded into four grades according to anatomical structures of the rabbit eye. The dose limiting toxicity was reached in group II after periocular injection of 30 mg of carboplatin and in group III after intravitreal injection of 0.05 mg of carboplatin. No systemic toxicity was observed in any group. Focal carboplatin administration may decrease systemic exposure to this cytotoxic drug in the retinoblastoma treatment. This moreover suggests that focal carboplatin administration is a promising approach and challenge for advanced retinoblastoma chemotherapy.

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