Current Drug Metabolism - Volume 19, Issue 12, 2018

Background: Clinical studies during pregnancy are rare due to ethical and practical limitations. Giving pregnant females the same dosing regimen used in adult males or nonpregnant females is inappropriate. Pregnancy physiologically-based pharmacokinetic modeling is a powerful tool that can be used to refine pharmacotherapy during pregnancy. Objective: This work provides a review of the current status of application of physiologically based pharmacokinetic models in developing dosing regimens in pregnant women. Methods: A structured search was done on Scholar Google, Science Direct and PubMed. The articles searched were those providing physiological, anatomical and biochemical data needed for pregnancy physiologically-based pharmacokinetic models or utilizing these models to evaluate the effect of pregnancy on drugs pharmacokinetics. Key words used for search include: PBPK and pregnancy, pharmacokinetic during pregnancy, ethics of pregnancy studies. The found articles were evaluated in terms of main pharmacokinetic features of the drug that were affected by pregnancy, the structure of the model, the software platform used and quality of predicted maternal and fetal exposure. Results: Pregnancy physiologically-based pharmacokinetic models can be used to optimize effective and safe dosing regimens needed during pregnancy. Different model structures have been successfully used for this purpose using different modeling software. Conclusion: More work is needed to fill the gaps in knowledge needed to more accurately and mechanistically simulate simultaneous exposure of the pregnant mother and her fetus/ embryo to drugs using pregnancy physiologicallybased pharmacokinetic modeling approach.

Background: Increasing incidences of type 2 diabetes make it necessary to have a better understanding of the risk factors for its prediction. Taking a note of resilience in risk factors, dynamics of the emerging factors other than traditional ones are showing a great interest in recent years which imprints a significant contribution in the occurrence of diabetes. Of different factors, sleep duration was acknowledged as a most common risk factor for diabetes. Methods: Adhering to the state of information available, studies recruited between 2010- 2016 a total of seven prospective studies including systematic review and meta-analysis were used to establish the relationship between sleep duration and type 2 diabetes. Studies were identified from Medline and Scopus. Studies included in this review was considered based on the different aspects such as maximum follow-up period, number of participants, including both sexes along with similar reference criteria of sleep duration. Results: With U-shaped association between sleep duration and the onset of diabetes, both short and long-term sleep duration was found contributing to the development of type 2 diabetes. Additionally, studies on the sex-related difference and pervasiveness of diabetes have also reported a profound relationship between short and long sleep hours and risk of developing type 2 diabetes. Conclusion: Our study supports other studies on the relationship between total sleep duration and the risk of developing type 2 diabetes. This review emphasizes the importance of total sleep duration, sleep quality as a risk marker in monitoring type 2 diabetes.

Background: Nitidine is a bioactive plant benzophenanthridine alkaloid isolated from the root of Zanthoxylum nitidum. Since its discovery in 1959, literature revealed marked anticancer, neuroprotective, antimalarial, anti-HIV, analgesic, anti-inflammatory and antifungal activities. However, its clinical status is not defined yet. Methods: Various scientific search engines were used for the available literature All the peer-reviewed journals were considered in this review. MOE (molecular operating environment) ligand-based pharmacophores features of nitidine were also studied to determine the various targeted sites in the molecule. Results: The search revealed an outstanding therapeutic potential in terms of various pharmacological effects of the molecule. MOE (Molecular Operating Environment) ligand-based pharmacophores features of nitidine showed that it has got multiple bioactive functional sites that implicate its sensitivity towards several receptors protein and therefore could be a useful lead compound. Despite having an outstanding therapeutic potential, it is not subjected to clinical trial yet, probably, due to host toxicity and being a quaternary salt, charged at all body pH values, and therefore, absorption through the gastro-intestinal-tract could be an issue. Conclusion: The issues can be resolved while applying latest pharmaceutical technologies, synthesizing its derivatives and subsequent clinical studies and thus could lead to the discovery of new clinically effective molecule(s).

Background: Pathogenic microbes routinely keep encountering different types of stress in their environment such as high osmolarity, high temperature, pH fluctuations in host gut etc. They tend to acquire certain small molecular weight molecules, termed osmolytes, so as to handle these challenges and survive in harsh conditions. These osmolytes include some which are self-synthesized by the microorganisms, while majority of them are imbibed from the external environment via osmolyte transporters. Methods: In this review, we have discussed work done on osmolytes and their transport systems, which influence upon sustenance and virulence of the pathogens under the given stress conditions. Results: Osmolytes and their transport systems play vital role in efficient maintenance of cell turgidity and electrolyte levels for proper cell functioning. These molecules don't disturb normal metabolic processes within the microbial cell at all; it rather stabilizes the macromolecules, such as nucleic acids and proteins. Besides, these osmolytes also empower the microbes with the pathogenicity potential under harsh conditions such as salt, pH, temperature stress, and the efficient host immunity. Conclusion: Exploring avenues with respect to osmolyte transport systems is the need of the hour especially in this time where we are facing the evolution of antibiotic resistance in pathogens. Most interestingly, a detailed study of bacterial stress responses would prove to be useful in comprehending what these pathogens face in the host microenvironment, whereby we can manipulate the pathogen survival in human gut, and hence address the menace of pathogenic resistance in humans as well as animals.

Background: Liver ailments including alcoholic liver disease (ALD), still remain the main reason for morbidity & mortality worldwide. In fact, ALD is a multifactorial disease with complex pathophysiology which is linked to several types of liver damages including steatohepatitis, fibrosis and cirrhosis. Methods: This review emphasizes on 30 herbal medicinal plants with their extracts studied for protective effect against ALD and current scientific evidence of ALD cure by thirty Indian Materia Medica including Tilia Platyphyllos, Amomum subulatum, Carica papaya, Pogostemon patchouli, Commelina benghalensis, Bacopamonnieri, Pecan nut, Allium cepa, Beta Vulgaris, Adina cordifolia, Ocimum gratissimum, Vernonia amygdalina, Sida veronicaefolia, Chenopodium album, Korean red ginseng, Elephantopus scaber, Tecomella undulata, Prunus armeniaca, Sea tangle (Laminaria japonica), Emblica officinalis, Saccharum officinarum, Cocculus hirsutus, Cassia roxburghii, Zhi-Zi-Da- Huang, Phyllanthus amarus, Aegle marmelos, Agrimonia eupatoria, Flaveria trinervia, Curcuma longa and Garcinia indica. Results: Reduction in oxidative stress, improvement in inflammation, reduction in degeneration of fat and necrosis are some of the mechanisms of action of these medicinal plants observed in alcohol induced in-vivo and in-vitro liver injury models. Conclusion: Accordingly, this review provides several evidences which show that these medicinal plants could be used for the treatment and prevention of ALD.

Background: Thiazides are the most commonly used medications for the treatment of mild and moderate hypertension. Despite their recognized effect, the mechanism by which thiazides reduce systemic blood pressure remains uncertain. The prevailing belief is that thiazides reduce blood pressure primarily via enhancement of salt excretion consequent to the inhibition of the Na-Cl Cotransporter (NCC) in the Distal Convoluted Tubules (DCT). However, recent reports point to a reduction in peripheral vascular resistance as a major mechanism of antihypertensive effect of thiazides. It is plausible that both mechanisms, renal and extra-renal, may be operating simultaneously. Recent studies point to compensatory mechanisms in the kidney distal nephron that may play a role in blunting the diuretic effect of thiazides. Not much information is available about the efficacy of thiazides in controlling blood pressure in individuals with Chronic Kidney Disease (CKD). Objective: This review will discuss the latest updates on the use and efficacy of thiazides derivatives as diuretics and antihypertensive medications in CKD patients. Conclusion: Thiazides remain effective as diuretics and antihypertensive agents in individuals with low GFR.

Background: Breast Cancer Resistance Protein (BCRP, also known as ABCG2) is gaining momentum as a key transporter that restricts the permeability of a large number of therapeutic agents through the Blood-brain Barrier (BBB). BCRP is highly expressed in the apical membranes of epithelial cells of the small and large intestine, renal proximal tubules and canalicular membrane of hepatocytes, determining the gastrointestinal absorption and biodisposition of its substrates. It is also expressed in the luminal surface of endothelial cells of the BBB and Bloodspinal Cord Barrier (BSCB), where it undoubtedly limits the entry of a wide range of therapeutics into the CNS, potentially contributing to the therapeutic failure of CNS-acting drugs. Methods: As the U.S. Food and Drug Administration and the European Medicines Agency recommend pre-clinical evaluation and clinical assessment of BCRP-mediated drug-drug interactions, compounds that are currently recognized as BCRP substrates, inhibitors or inducers will be addressed, focusing on their pharmacokinetic behaviour in plasma and brain. Results: Recent studies indicated a strong BCRP expression in the microvasculature of the BBB in brain tumors, hypothesizing that this phenomenon critically influences the penetration of drugs in these tumors and potentially contributes to the failure of antitumor therapy. BCRP expression in brain tissue from patients or animal models of neurological and neurodegenerative diseases has also been investigated, and the role of BCRP and its implications for novel therapeutic interventions was also herein demonstrated. Conclusions: The clinical significance of BCRP in drugs disposition is currently undeniable.

Background: The endocrine system of vitamin D is involved in an extensive variety of biological processes such as bone metabolism, regulation of cell proliferation and differentiation and modulation of the immune response. The active form of vitamin D, 25-hydroxyvitamin D, binds to vitamin D receptor (VDR) controlling the synthesis of many different proteins. Although numerous studies reported polymorphism in the VDR gene, the impact of the polymorphic alleles on VDR protein function remains unknown. Methods: We presented a comprehensive review of the evidence on the role of genetic polymorphisms, especially those of VDR, in vitamin D-related disorders including their clinical implications. Relevant papers we identified be an extensive search of bibliographic databases using appropriate keywords. Results: VDR gene variants seem to influence many biological endpoints, including those related to osteoporosis. BsmI, ApaI, and TaqI are the three adjacent single nucleotide polymorphisms in the VDR gene which have been most frequently studied so far. These polymorphisms are apparently nonfunctional, and one or more functional polymorphism elsewhere in the VDR gene, and linkage disequilibrium may explain the association between VDR genes polymorphisms and common diseases. Conclusion: In different study populations, different alleles of the anonymous restriction fragment length polymorphisms can be found associated with the same endpoint. This effect probably reflects that linkage disequilibrium, between the anonymous marker alleles and the causative alleles in (or very near) the VDR gene, is likely to be different between populations.