The dromedary camel (Camelus dromedarius), a unique animal highly adapted to the desert ecosystem, can digest a range of plant materials, including low-quality shrubs and trees. This ability can be attributed to the extensive microbial population in the forestomach comprising bacteria, archaea, fungi, and protozoa (Bhatt et al. 2013). The digestive anatomy and physiology of the dromedary camel is different from that of true ruminants like cattle, sheep, and goat. The forestomach of camel comprises only three chambers (C1, C2, and C3), while in true ruminants, four chambers are present (Fowler 2010). Chamber C1 is a large anaerobic fermentation chamber analogous to the rumen in function and harbors a distinct microbial community that enables the camel to digest, ferment, and extract the nutrients efficiently from plant lignocellulosic material (Kay and Maloiy 1989). Studies suggest that the camel rumen microbiome is structurally similar but compositionally distinct from other ruminants (Gharechahi et al. 2015; Dande et al. 2015). At the phylum level, Firmicutes comprises the second largest group, accounting for about 31% of the total bacterial population in camel rumen (Gharechahi et al. 2015).
There are inherent structural and functional differences in the central nervous systems (CNS) of females and males. It has been gradually established that these sex-specific differences are due to a spectrum of genetic, epigenetic, and hormonal factors which actively contribute to the differential incidences, disease courses, and even outcomes of CNS diseases between sexes. Microglia, as principle resident macrophages in the CNS, play a crucial role in both CNS physiology and pathology. However, sex differences of microglia have been relatively unexplored until recently. Emerging data has convincingly demonstrated the existence of sex-dependent structural and functional differences of rodent microglia, consequently changing our current understanding of these versatile cells. In this review, we attempt to comprehensively outline the current advances revealing microglial sex differences in rodent and their potential implications for specific CNS diseases with a stark sex difference. A detailed understanding of molecular processes underlying microglial sex differences is of major importance in design of translational sex- and microglia-specific therapeutic approaches.
Vd Joshi Physiology Pdf 11
Sex differences of microglia exist among diverse regions with respect to both CNS physiology and pathology. Sexual microglial dimorphism may be in part responsible for sex differences in the incidence and pathology of a variety of neurological diseases. Males may be more vulnerable to neurological insults during early development in part as a result of having more highly activated microglia in the developing brain compared to females. In contrast, increased activation of microglia in females during adulthood may contribute to their increased susceptibility to several inflammatory brain diseases that occur late in life. Given our increasing understanding of these fascinating cells in some degree of both targets and drivers of sex differentiation [108], future investigation will bear exciting novel discoveries about sex microglia. Sex differences of microglia could be caused by intrinsic differences evidenced by X chromosome containing a large density of immune-related genes and some epigenetic modifiers, while the differences can also be mediated by hormonal or other environmental influences expressed over the lifespan. Therefore, more effort will be needed to explore how genes located on the X or Y chromosomes, epigenetic mechanisms, endocrine factors, and microenvironmental signals synergistically contribute to microglial sex differences and then fully understand the molecular bias of CNS diseases with sex vulnerability [108, 109].
The development of generic ophthalmic drug products is challenging due to the complexity of the ocular system, and a lack of sensitive testing to evaluate the interplay of physiology with ophthalmic formulations. While measurements of drug concentration at the site of action in humans are typically sparse, these measurements are more easily obtained in rabbits. The purpose of this study is to demonstrate the utility of an ocular physiologically based pharmacokinetic (PBPK) model for translation of ocular exposure from rabbit to human.
Physiologically based pharmacokinetic (PBPK) models were first introduced in the 1970s to support drug product development from preclinical to clinical trials as they can reduce cost and attrition in drug product development [7, 8]. PBPK models are now routinely used by the pharmaceutical industry to predict first-in-human doses for oral formulations based on preclinical data [9], to predict drug-drug interactions based on in vitro parameters, or to support formulation optimization based on in vitro dissolution data [10]. The numerous applications of PBPK models in the generic industry have been presented elsewhere [11]. Ocular PBPK models can provide an insight into drug partitioning in eye tissues that are not accessible and/or are challenging to sample in humans and serve as an alternative methodology to study ophthalmic drugs PK and PD. The rabbit eye physiology is comparable to human eye physiology [12] and this animal is used as the main preclinical model to investigate the impact of formulation changes on an API ocular exposure. This physiological resemblance makes rabbit the preferred species for PBPK-based extrapolation of human ocular exposure based on preclinical data [12].
The default ocular physiologies for NZ and DB rabbits available in GastroPlus version 9.8.2 were used for model development and validation. As described above, rabbit-to-human extrapolation was then performed by switching the DB rabbit physiology to the default human ocular physiology available in GastroPlus version 9.8.2. For all studies, the dose administered volume, and dosing schedules were adjusted based on the information reported in the literature.
The clinical extrapolations were performed using the validated OCAT drug-specific parameters from rabbit simulations. The physiological parameters were adjusted to match human ocular physiology. In addition, the dose, dose volume, and dosing regimen were parameterized to match the published information for each human trial. Clinical data were obtained from patients undergoing either cataract, keratoplasty, or vitrectomy surgeries. Additionally, conjunctival biopsies in healthy subjects were available. Based on the surgical procedure, sampling from different ocular tissues is performed: AH for cataract and cornea and AH for keratoplasty; AH and VH for vitrectomy; and conjunctiva in healthy subject conjunctival biopsies. The sources, study protocols, and disease conditions for all clinical studies are listed in supplementary material 2. To assess the ability of the OCAT model to predict human ocular exposure, individual simulations were performed for each study, and results were compared with the corresponding observed data. Most of the published clinical studies were performed on patients. At this stage, the disease conditions were not accounted for in the ophthalmic physiology. To understand if the disease condition could impact the in silico extrapolation, clinical studies were pooled based on the type of surgery performed.
An understanding of the ocular absorption mechanism is necessary for both the pharmaceutical industry and the regulatory agencies to support the development and evaluation of new and generic drug products. A previous research project described the methodology to develop and validate an OCAT model for a rabbit physiology [1]. That project was focused solely on rabbit data and was a proof of concept of the benefits of in silico approaches to support the development of ophthalmic drug products. The current study builds upon the previous project and demonstrates the ability of the OCAT model to predict human ocular exposure. This is achieved by performing PK extrapolation using a validated PBPK model based on rabbit data for three APIs formulated as topical ophthalmic solutions. Additionally, this study proposes a strategy to perform model-based clinical extrapolation for ophthalmic solutions.
The current version of the human ocular physiology describes a healthy eye. Yet, a large portion of the observed clinical data is obtained from patients. The impact of disease on exposure of APIs may be a key factor to consider.
Based on the Center for Disease Control and Prevention (CDC), cataract is a clouding of the lens in the eye that affects vision [36]. This disease is multifactorial but aging is known to be the major cause [37]. Age-mediated changes of the ocular physiology are not implemented in the current version of the OCAT model. However, age-dependent changes in the tear proteome [38], the tear function in a normal population [39], and tear composition [40] have been reported. Therefore, the pathophysiology itself only affects the lens, which is a non-vascularized ocular tissue, and this is not expected to have an impact on the extrapolation process. Nevertheless, the age of the patients participating in the clinical trial could impact the predictions as their tear drainage system may present differences to a typical healthy individual. Future work focusing on the age-mediated evolution of the ocular physiology will be needed.
Initial establishment of the human gut microbiota is generally believed to occur immediately following birth, involving key gut commensals such as bifidobacteria that are acquired from the mother. The subsequent development of this early gut microbiota is driven and modulated by specific dietary compounds present in human milk that support selective colonization. This represents a very intriguing example of host-microbe co-evolution, where both partners are believed to benefit. In recent years, various publications have focused on dissecting microbial infant gut communities and their interaction with their human host, being a determining factor in host physiology and metabolic activities. Such studies have highlighted a reduction of microbial diversity and/or an aberrant microbiota composition, sometimes referred to as dysbiosis, which may manifest itself during the early stage of life, i.e., in infants, or later stages of life. There are growing experimental data that may explain how the early human gut microbiota affects risk factors related to adult health conditions. This concept has fueled the development of various nutritional strategies, many of which are based on probiotics and/or prebiotics, to shape the infant microbiota. In this review, we will present the current state of the art regarding the infant gut microbiota and the role of key commensal microorganisms like bifidobacteria in the establishment of the first microbial communities in the human gut. 2ff7e9595c
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