Review

Authors: Hector F DeLuca

Vitamin D3 is a prohormone produced in skin through ultraviolet irradiation of 7-dehydrocholesterol. It is biologically inert and must be metabolized to 25-hydroxyvitamin D3 in the liver and then to 1alpha,25-dihydroxyvitamin D3 in the kidney before function. The hormonal form of vitamin D3, ie, 1alpha,25-dihydroxyvitamin D3, acts through a nuclear receptor to carry out its many functions, including calcium absorption, phosphate absorption in the intestine, calcium mobilization in bone, and calcium reabsorption in the kidney. It also has several noncalcemic functions in the body. This overview provides a brief description of the physiologic, endocrinologic, and molecular biologic characteristics of vitamin D. It also provides information on new selective analogs of 1alpha,25-dihydroyvitamin D3 for therapy.

Topics: Bone and Bones; Calcitriol; Calcium; Cholecalciferol; Humans; Intestinal Absorption; Kidney; Phosphates; Vitamin D; Vitamin D Deficiency

PubMed: 15585789
DOI: 10.1093/ajcn/80.6.1689S

Authors: Sonja Bergmann, Sean E Lawler, Yuan Qu...

In vitro models of the blood-brain barrier (BBB) are critical tools for the study of BBB transport and the development of drugs that can reach the CNS. Brain endothelial cells grown in culture are often used to model the BBB; however, it is challenging to maintain reproducible BBB properties and function. 'BBB organoids' are obtained following coculture of endothelial cells, pericytes and astrocytes under low-adhesion conditions. These organoids reproduce many features of the BBB, including the expression of tight junctions, molecular transporters and drug efflux pumps, and hence can be used to model drug transport across the BBB. This protocol provides a comprehensive description of the techniques required to culture and maintain BBB organoids. We also describe two separate detection approaches that can be used to analyze drug penetration into the organoids: confocal fluorescence microscopy and mass spectrometry imaging. Using our protocol, BBB organoids can be established within 2-3 d. An additional day is required to analyze drug permeability. The BBB organoid platform represents an accurate, versatile and cost-effective in vitro tool. It can easily be scaled to a high-throughput format, offering a tool for BBB modeling that could accelerate therapeutic discovery for the treatment of various neuropathologies.

Topics: Astrocytes; Biological Transport; Blood-Brain Barrier; Cell Line; Coculture Techniques; Endothelial Cells; Humans; Microscopy, Confocal; Microscopy, Fluorescence; Optical Imaging; Organoids; Pericytes; Permeability; Pharmaceutical Preparations; Pharmacokinetics; Small Molecule Libraries; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

PubMed: 30382243
DOI: 10.1038/s41596-018-0066-x

Authors: G Shankar, S Arkin, L Cocea...

Immunogenicity is a significant concern for biologic drugs as it can affect both safety and efficacy. To date, the descriptions of product immunogenicity have varied not only due to different degrees of understanding of product immunogenicity at the time of licensing but also due to an evolving lexicon that has generated some confusion in the field. In recent years, there has been growing consensus regarding the data needed to assess product immunogenicity. Harmonization of the strategy for the elucidation of product immunogenicity by drug developers, as well as the use of defined common terminology, can benefit medical practitioners, health regulatory agencies, and ultimately the patients. Clearly, understanding the incidence, kinetics and magnitude of anti-drug antibody (ADA), its neutralizing ability, cross-reactivity with endogenous molecules or other marketed biologic drugs, and related clinical impact may enhance clinical management of patients treated with biologic drugs. To that end, the authors present terms and definitions for describing and analyzing clinical immunogenicity data and suggest approaches to data presentation, emphasizing associations of ADA development with pharmacokinetics, efficacy, and safety that are necessary to assess the clinical relevance of immunogenicity.

Topics: Antibody Formation; Guidelines as Topic; Humans; Peptides; Proteins; Terminology as Topic

PubMed: 24764037
DOI: 10.1208/s12248-014-9599-2

Review

Authors: Christian S Wright, Alexander G Robling, Mary C Farach-Carson...

Voltage-sensitive calcium channels (VSCCs) are ubiquitous multimeric protein complexes that are necessary for the regulation of numerous physiological processes. VSCCs regulate calcium influx and various intracellular processes including muscle contraction, neurotransmission, hormone secretion, and gene transcription, with function specificity defined by the channel's subunits and tissue location. The functions of VSCCs in bone are often overlooked since bone is not considered an electrically excitable tissue. However, skeletal homeostasis and adaptation relies heavily on VSCCs. Inhibition or deletion of VSCCs decreases osteogenesis, impairs skeletal structure, and impedes anabolic responses to mechanical loading. RECENT FINDINGS: While the functions of VSCCs in osteoclasts are less clear, VSCCs have distinct but complementary functions in osteoblasts and osteocytes. PURPOSE OF REVIEW: This review details the structure, function, and nomenclature of VSCCs, followed by a comprehensive description of the known functions of VSCCs in bone cells and their regulation of bone development, bone formation, and mechanotransduction.

Topics: Animals; Bone and Bones; Calcium Channels; Humans; Tissue Distribution

PubMed: 33721180
DOI: 10.1007/s11914-020-00647-7

Review

Authors: Dominique Lunter, Victoria Klang, Dorottya Kocsis...

The analytical technology of Raman spectroscopy has an almost 100-year history. During this period, many modifications and developments happened in the method like discovery of laser, improvements in optical elements and sensitivity of spectrometer and also more advanced light detection systems. Many types of the innovative techniques appeared (e.g. Transmittance Raman spectroscopy, Coherent Raman Scattering microscopy, Surface-Enhanced Raman scattering and Confocal Raman spectroscopy/microscopy). This review article gives a short description about these different Raman techniques and their possible applications. Then, a short statistical part is coming about the appearance of Raman spectroscopy in the scientific literature from the beginnings to these days. The third part of the paper shows the main application options of the technique (especially confocal Raman spectroscopy) in skin research, including skin composition analysis, drug penetration monitoring and analysis, diagnostic utilizations in dermatology and cosmeto-scientific applications. At the end, the possible role of artificial intelligence in Raman data analysis and the regulatory aspect of these techniques in dermatology are briefly summarized. For the future of Raman Spectroscopy, increasing clinical relevance and in vivo applications can be predicted with spreading of non-destructive methods and appearance with the most advanced instruments with rapid analysis time.

Topics: Artificial Intelligence; Microscopy, Confocal; Skin; Skin Absorption; Spectrum Analysis, Raman

PubMed: 35837832
DOI: 10.1111/exd.14645

Review

Authors: Hua Xu, Fayez K Ghishan, Pawel R Kiela...

The Slc9 family of Na /H exchangers (NHEs) plays a critical role in electroneutral exchange of Na and H in the mammalian intestine as well as other absorptive and secretory epithelia of digestive organs. These transport proteins contribute to the transepithelial Na and water absorption, intracellular pH and cellular volume regulation as well as the electrolyte, acid-base, and fluid volume homeostasis at the systemic level. They also influence the function of other membrane transport mechanisms, affect cellular proliferation and apoptosis as well as cell migration, adherence to the extracellular matrix, and tissue repair. Additionally, they modulate the extracellular milieu to facilitate other nutrient absorption and to regulate the intestinal microbial microenvironment. Na /H exchange is inhibited in selected gastrointestinal diseases, either by intrinsic factors (e.g., bile acids, inflammatory mediators) or infectious agents and associated bacterial toxins. Disrupted NHE activity may contribute not only to local and systemic electrolyte imbalance but also to the disease severity via multiple mechanisms. In this review, we describe the cation proton antiporter superfamily of Na /H exchangers with a particular emphasis on the eight SLC9A isoforms found in the digestive tract, followed by a more integrative description in their roles in each of the digestive organs. We discuss regulatory mechanisms that determine the function of Na /H exchangers as pertinent to the digestive tract, their regulation in pathological states of the digestive organs, and reciprocally, the contribution of dysregulated Na /H exchange to the disease pathogenesis and progression. © 2018 American Physiological Society. Compr Physiol 8:555-583, 2018.

Topics: Animals; Digestive System; Gastrointestinal Diseases; Gene Expression Regulation; Humans; Intestinal Absorption; Salivary Glands; Sodium-Hydrogen Exchangers

PubMed: 29687889
DOI: 10.1002/cphy.c170027

Review

Authors: Daniel Cristian Ferreira Soares, Fernanda Poletto, Marcelo J Eberhardt...

The emergence of many new viruses in recent times has resulted in a significant scientific challenge for discovering drugs and vaccines that effectively treat and prevent viral diseases. Nanotechnology has opened doors to prevent the spread of several diseases, including those caused by viruses. Polymer-hybrid nanodevices are a class of nanotechnology platforms for biomedical applications that present synergistic properties among their components, with improved performance compared to conventional forms of therapy. Considering the growing interest in this emerging field and the promising technological advantages of polymer-hybrid nanodevices, this work presents the current status of these systems in the context of prevention and treatment of viral diseases. A brief description of the different types of polymer-hybrid nanodevices highlighting some peculiar characteristics such as their composition, biodistribution, delivery of antigens, and overall immune responses in systemic tissues are discussed. Finally, the work presents the future trends for new nanotechnological hybrid materials based on polymers and perspectives for clinical use.

Topics: Animals; Antiviral Agents; Drug Delivery Systems; Humans; Immunity, Cellular; Nanoparticles; Nanotechnology; Polymers; Tissue Distribution; Virus Diseases

PubMed: 34972632
DOI: 10.1016/j.biopha.2021.112249

Authors: M R Hesse, J R Prins, M N Lub-de Hooge...

BACKGROUND AND OBJECTIVE

Pharmacokinetics (PK) are severely altered in pregnant women due to changes in volume of distribution (Vd) and/or drug clearance (CL), affecting target attainment of antibiotics in pregnant women. This review is part of a series that reviews literature on the description of PK and target attainment of antibiotics in pregnant women with specific focus on penicillins.

METHODS

A systematic literature search was carried out in PubMed. Articles were labelled as relevant when information on PK of penicillins in pregnant women was available.

RESULTS

Thirty-two relevant articles were included, 8 of which discussed amoxicillin (with and without clavulanic acid), 15 ampicillin, 4 benzylpenicillin, 1 phenoxymethylpenicillin, and 4 piperacillin (with and without tazobactam). No studies were found on pheneticillin and flucloxacillin in pregnant women. Ten out of 32 articles included information on both Vd and CL. During the second and third trimester of pregnancy, a higher CL and larger Vd was reported than in non-pregnant women and in pregnant women during first trimester. Reduced target attainment was described in second and third trimester pregnant women. Only 7 studies reported dosing advice, 4 of which were for amoxicillin.

CONCLUSION

The larger Vd and higher CL in second and third trimester pregnant women might warrant a higher dosage or shortening of the dosing interval of penicillins to increase target attainment. Studies frequently fail to provide dosing advice for pregnant women, even if the necessary PK information was available.

Topics: Pregnancy; Female; Humans; Penicillins; Anti-Bacterial Agents; Amoxicillin; Ampicillin; Piperacillin

PubMed: 36662480
DOI: 10.1007/s40262-023-01211-z

Review

Authors: Ana Y Simão, Mónica Antunes, Emanuel Cabral...

The emergence of new psychoactive substances has earned a great deal of attention, and several reports of acute poisoning and deaths have been issued involving, for instance, synthetic opiates. In recent years, there have been profound alterations in the legislation concerning consumption, marketing, and synthesis of these compounds; rapid alert systems have also been subject to changes, and new substances and new markets, mainly through the internet, have appeared. Their effects and how they originate in consumers are still mostly unknown, primarily in what concerns chronic toxicity. This review intends to provide a detailed description of these substances from the point of view of consumption, toxicokinetics, and health consequences, including case reports on intoxications in order to help researchers and public health agents working daily in this area.

Topics: Analgesics, Opioid; Illicit Drugs; Marketing; Psychotropic Drugs; Public Health

PubMed: 35457736
DOI: 10.3390/ijerph19084869

Review

Authors: Katarzyna Danis-Wlodarczyk, Krystyna Dąbrowska, Stephen T Abedon...

Pharmacology can be differentiated into two key aspects, pharmacodynamics and pharmacokinetics. Pharmacodynamics describes a drug's impact on the body while pharmacokinetics describes the body's impact on a drug. Another way of understanding these terms is that pharmacodynamics is a description of both the positive and negative consequences of drugs attaining certain concentrations in the body while pharmacokinetics is concerned with our ability to reach and then sustain those concentrations. Unlike the drugs for which these concepts were developed, including antibiotics, the bacteriophages (or 'phages') that we consider here are not chemotherapeutics but instead are the viruses of bacteria. Here we review the pharmacology of these viruses, particularly as they can be employed to combat bacterial infections (phage therapy). Overall, an improved pharmacological understanding of phage therapy should allow for more informed development of phages as antibacterial 'drugs', allow for more rational debugging of phage therapy experiments, and encourage improved design of phage therapy protocols. Contrasting with antibiotics, however, phages as viruses impact individual bacterial cells as single virions rather than as swarms of molecules, and while they are killing bacteria, bacteriophages also can amplify phage numbers, . Explorations of phage therapy pharmacology consequently can often be informed as well by basic principles of the ecological interactions between phages and bacteria as by study of the pharmacology of drugs. Bacteriophages in phage therapy thus can display somewhat unique as well as more traditional pharmacological aspects.

Topics: Anti-Bacterial Agents; Bacterial Infections; Bacteriolysis; Bacteriophages; Drug Resistance, Bacterial; Humans; Phage Therapy; Pharmacokinetics; Treatment Outcome

PubMed: 32503951
DOI: 10.21775/cimb.040.081