Predicting Resolvin D1 Pharmacokinetics in Humans with Physiologically‐Based Pharmacokinetic Modeling

Sjögren’s syndrome (SS) is an autoimmune disease with no effective treatment options. Resolvin D1 (RvD1) belongs to a class of lipid‐based specialized pro‐resolving mediators that showed efficacy in preclinical models of SS. We developed a physiologically‐based pharmacokinetic (PBPK) model of RvD1 in mice and optimized the model using plasma and salivary gland pharmacokinetic (PK) studies performed in NOD/ShiLtJ mice with SS‐like features. The predictive performance of the PBPK model was also evaluated with two external datasets from the literature reporting RvD1 PKs. The PBPK model adequately captured the observed concentrations of RvD1 administered at different doses and in different species. The PKs of RvD1 in virtual humans were predicted using the verified PBPK model at various doses (0.01–10 mg/kg). The first‐in‐human predictions of RvD1 will be useful for the clinical trial design and translation of RvD1 as an effective treatment strategy for SS.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Sjögren’s syndrome (SS) is a complex inflammatory disorder with no clinically approved treatment options. Resolvin D1 (RvD1), a specialized pro‐resolving mediator with potent anti‐inflammatory effects, has shown promise in preclinical studies to restore the salivary gland function and promote tissue repair.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ We leveraged physiologically‐based pharmacokinetic (PBPK) modeling to predict the RvD1 pharmacokinetics (PKs) in humans by extrapolation from PK data obtained from in vivo experiments in a mouse model of SS.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ The PBPK model provides an appropriate dose and estimates of clearance and other PK parameters for RvD1 in humans. These PK parameters and dose will inform the initial dosing of RvD1 for first‐in‐human clinical studies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ This study significantly advances the potential for clinical translation of RvD1 into clinical trials for the treatment of SS.

Sjögren’s syndrome (SS) is a chronic inflammatory autoimmune disease characterized by the diminished secretory function of the exocrine glands. ¹ It affects ~ 1% of the general population and up to 3% of people above the age of 50 years. ² Women account for > 90% of diagnosed cases. ² Diagnostic hallmarks for SS include xerostomia or dry mouth, impaired tear production, lymphocytic infiltration into salivary glands, and presence of anti‐Ro and anti‐La autoantibodies in plasma. ¹ SS reduces salivary gland function and leads to oral diseases, such as gingivitis and caries, and candidiasis. ³ The advanced complications of reduced salivary gland function include recurrent infection of the parotid gland ⁴ and lymphomas. ⁵ Together, these issues impose significant physical, psychological, and economic burdens on patients with SS. ⁶ Furthermore, the cause of SS is still unknown, and current therapeutic interventions are ineffective and limited to the use of saliva substitutes and medications that provide only temporary relief. ⁷ Therefore, the development of alternative treatments to restore salivary gland function are an urgent and unmet medical need.Viral and bacterial infections, in conjunction with the activation of susceptibility genes, stimulates chronic salivary gland inflammation. ⁸ A state of chronic inflammation causes tissue damage followed by cytokine and chemokine release. ⁸ When resolution mechanisms are working correctly, neutrophils and M2 macrophages can clear the site of injury or infection. ⁹ However, in SS, these resolution mechanisms are impaired, ¹⁰ and the dead cells involved in the process cannot be removed from the injury/infection site leading to the production of autoantigens and elevations in proinflammatory cytokine levels. ¹¹ The increased production of autoantigens and proinflammatory cytokines stimulate peripheral lymphocytes to bind to and infiltrate across the vascular endothelium into the salivary gland. ¹² Lymphocyte infiltration exacerbates the pathologic proinflammatory state, tissue damage, and hastens salivary gland dysfunction. ¹³ The cascade of events leading to inflammation resolution is an actively regulated process mediated in part by a family of endogenous lipid‐based specialized pro‐resolving mediators, which include resolvins, maresins, lipoxins, and protectins. ¹⁴ The administration of pro‐resolving lipid mediators have demonstrated efficacy in treating diseases having a pathologic proinflammatory basis, such as osteoarthritis, by terminating proinflammatory signaling, thereby enhancing tissue regeneration. ¹⁵ These pro‐resolving lipid mediators have been detected in animal models of infection and chronic inflammation. ¹⁶ Specific to SS, exogenous resolvin administration has the potential to reduce inflammation and restore salivary gland function. ¹⁷ Naturally occurring resolvin subtypes include the D series (derived from docosahexaenoic acid), the E series (derived from eicosapentaenoic acid), and six analogs of the D series, which are produced in response to aspirin. ¹⁸ Previously, we identified resolvin D1 (RvD1) as a therapeutic candidate for the treatment of SS. ¹⁹ RvD1 reduced inflammation and restored salivary gland tissue integrity in animal models of SS. ¹⁹ , ²⁰ , ²¹ In addition, the progression of SS‐like features in NOD/ShiLtJ mice can be halted using an aspirin‐triggered form of RvD1. In this circumstance, mice treated systemically, prior to disease onset, displayed downregulation of proinflammatory cytokines, upregulation of anti‐inflammatory mediators, and intact saliva production. ²² , ²³ Based on the preclinical safety and efficacy data of RvD1, we are preparing for phase I studies in humans. Therefore, the purpose of this study was to perform first‐in‐human predictions of RvD1 pharmacokinetics (PKs) in plasma and saliva using a verified whole‐body physiologically‐based pharmacokinetic (PBPK) model. The mouse PBPK model of RvD1 was developed using the physical, chemical, and biological properties of RvD1 and was optimized with plasma and salivary gland PK data obtained in SS‐like mice. The mouse PBPK model was then extrapolated to humans to generate appropriate first‐in‐human dose predictions.     

Role of the anterior insular cortex in integrative causal signaling during multisensory auditory–visual attention

Coordinated attention to information from multiple senses is fundamental to our ability to respond to salient environmental events, yet little is known about brain network mechanisms that guide integration of information from multiple senses. Here we investigate dynamic causal mechanisms underlying multisensory auditory–visual attention, focusing on a network of right‐hemisphere frontal–cingulate–parietal regions implicated in a wide range of tasks involving attention and cognitive control. Participants performed three ‘oddball’ attention tasks involving auditory, visual and multisensory auditory–visual stimuli during fMRI scanning. We found that the right anterior insula (rAI) demonstrated the most significant causal influences on all other frontal–cingulate–parietal regions, serving as a major causal control hub during multisensory attention. Crucially, we then tested two competing models of the role of the rAI in multisensory attention: an ‘integrated’ signaling model in which the rAI generates a common multisensory control signal associated with simultaneous attention to auditory and visual oddball stimuli versus a ‘segregated’ signaling model in which the rAI generates two segregated and independent signals in each sensory modality. We found strong support for the integrated, rather than the segregated, signaling model. Furthermore, the strength of the integrated control signal from the rAI was most pronounced on the dorsal anterior cingulate and posterior parietal cortices, two key nodes of saliency and central executive networks respectively. These results were preserved with the addition of a superior temporal sulcus region involved in multisensory processing. Our study provides new insights into the dynamic causal mechanisms by which the AI facilitates multisensory attention.     

Expression and regulatory role of GAIP-interacting protein GIPC in pancreatic adenocarcinoma

Regulator of G-protein signaling-GAIP-interacting protein COOH terminus (GIPC) is involved in protein trafficking, endocytosis, and receptor clustering and is associated with insulin-like growth factor I receptor (IGF-IR), a receptor important for proliferation and anchorage-independent growth. Here, we described GIPC expression in different human pancreatic adenocarcinoma (PCA) cell lines and we examined the role of GIPC in the regulation of IGF-IR protein levels in PCA. Interestingly, inhibition of GIPC expression by RNA interference led to reduced IGF-IR protein levels and a subsequent decrease in proliferation of PCA cells. We also determined that the PDZ domain of GIPC is essential for the post-translational regulation and the binding of IGF-IR. The importance of GIPC in pancreatic cancer development and progression is supported by tissue microarray data of 300 pancreatic cancer specimens where GIPC is highly expressed in PCA. Taken together, our data suggest that GIPC is a central molecule for the stability of IGF-IR and could be a target for future therapy.     

Covered coronary stent grafts as a treatment option for carotid-cavernous fistulas: our initial experience

Treatment of Type 1 carotid-cavernous fistula (CCF) is complex and endovascular stent grafting is proving to be an excellent technique not only in successful treatment of fistula but also preserving patency of parent artery. We describe our initial experience in the use of covered coronary stent grafts in the treatment of three patients with Type 1 post-traumatic CCF. All patients were successfully treated with placement of stent grafts. Immediate closure of fistula was achieved in all the three patients. One patient developed partial in-stent thrombosis. In this patient antiplatelet therapy had to be stopped as he developed a small intracerebral hematoma post procedure. Subsequently, he was restarted on antiplatelets and recovered completely. Except for this no other complication was observed. Covered stent grafts may be the procedure of choice for treatment of post-traumatic Type 1 CCF especially in young patients with favorable anatomy.     

Digitally assisted three-dimensional surgery – Beyond vitreous

Purpose:The aim of this study was to evaluate the application and safety of three-dimensional (3D) visualization system in varied anterior segment procedures and Scleral Buckle.Methods:This was a prospective observational study of 313 eyes. Patients undergoing phacoemulsification (PE) with intraocular lens (IOL), trabeculectomies, glaucoma triple procedure (GTP), scleral fixated (SF) IOL, and scleral buckle (SB) were included in the study. Cases were randomly distributed in 3D visualization system (learning and post-learning phase) and conventional microscope group. Parameters studied were complications (intraoperative and early postoperative), surgical outcomes, and surgeon’s perspective on various parameters (through a validated questionnaire) like surgical time, time lag, learning curve, ease of doing various steps and its value as an educational tool, for both groups [Questionnaires 1 and 2].Results:Complications rates were not different in two groups. Surgical outcomes (anatomical and physiological) were similar in both the groups. Mean duration of surgery in PE+IOL, Trabeculectomy, GTP in learning stage by 3D was significantly higher than Microscope, which became insignificant in postlearning stage. For, SB and SFIOL, duration between two groups were insignificantly different. There was significant learning struggle in PE+IOL, SB, and Trabeculectomy. Image resolution, depth perception, illumination and postural comfort was graded higher for 3D surgery across the stages. Time lag, poor color contrast, and field of view were appreciated during the learning stage. Educational relevance of 3D was higher, as appreciated by resident and nurses.Conclusion:3D surgery is as safe, faster, and predictable after initial learning struggle. Even in anterior segment procedure, no apparent lag was appreciated after learning curve.     

Occult oncocytoma of the lacrimal sac

Oncocytoma of the lacrimal sac is a rarely encountered clinical entity. We report the case of a 72-year-old female patient who was diagnosed to have bilateral nasolacrimal duct obstruction during a pre-cataract surgery screening. Subsequently, she underwent bilateral dacryocystectomy. Histopathological examination of the left lacrimal sac revealed a tumour composed of acini lined by oncocytic cells; features consistent with those of a lacrimal sac oncocytoma. Although rare, oncocytomas arising from the lacrimal sac may co-exist with a nasolacrimal duct obstruction. This report describes the histological and immunochemistry characteristics of oncocytomas and underscores the need to subject all excised lacrimal sacs to histopathological examination.     

Pulsed-laser-induced damage in rat corneas: time-resolved imaging of physical effects and acute biological response

Laser-induced damage is studied in the rat corneal epithelium and stroma using a combination of time-resolved imaging and biological assays. Cavitation bubble interactions with cells are visualized at a higher spatial resolution than previously reported. The shock wave is observed to propagate through the epithelium without cell displacement or deformation. Cavitation bubble expansion is damped in tissue with a reduction in maximum size in the range of 54 to 59%, as compared to 2-D and 3-D cultures. Bubble expansion on nanosecond timescales results in rupture of the epithelial sheet and severe compression of cell layers beyond the bubble rim. In the stroma, the dense collagen lamellae strongly damped bubble expansion, thus resulting in reduced damage. The acute biological response of this tissue to laser pulses is characterized by confocal fluorescence microscopy. A viability assay of the epithelium reveals that only cells around the immediate site of laser focus are killed, while cells seen to undergo large deformations remain alive. Actin morphology in cells facing this mechanical stress is unchanged. Collagen microstructure in the stroma as revealed by second-harmonic imaging around the ablation site shows minimal disruption. These cellular responses are also compared to in vitro 2-D and 3-D cell cultures.     

Early victims of X-rays: a tribute and current perception

X-rays were discovered in 1895 and since then much has been written about Wilhelm Roentgen and the events surrounding the discovery. However, there have been only scattered references in the literature about the early workers who dedicated their life, and death, to X-rays. Radiology has come of age since then. Large exposure times have been reduced to milliseconds and there has been a change from analogue to digital. The advent of new and rapidly developing modalities and the ubiquitous presence of cone beam CT (CBCT) highlight the need to remember the early victims of X-rays, especially with the lack of universal guidelines for taking a CBCT scan. The aim of this article is to alert the oral radiologist to exposing patients irrespective of need, and to pay respect to the victims on the 116(th) anniversary of the discovery of X-rays.     

The role of maxillofacial radiologists in gunshot injuries: a hypothesized missile trajectory in two case reports

Gunshot injuries are an emerging form of trauma that oral radiologists increasingly have to deal with. There are two main types of gunshot injuries: high-velocity and low-velocity bullet injuries. The outcome of high-velocity gunshot injury is usually fatal; however, a non-fatal low-velocity injury to the maxillofacial region is more likely to be encountered by the oral and maxillofacial radiologist. It is therefore important to up-to-date knowledge of ballistic science and its implications in the field of maxillofacial radiology. The ability of oral and maxillofacial radiologists to predict the missile trajectory will aid the assessment and localization of the damage caused by the bullet and its splinters. Predicting the missile trajectory may also be of help to law enforcement agencies and forensic scientists in determining the type of firearm used and direction of fire. This article, which examines two cases, attempts to highlight to the oral radiologist this emerging form of trauma and its implications.