Ontogeny of rat CYP2E1 and CYP1A2 : a characterization and a pharmacokinetic model

Infantile exposure to xenobiotics, e.g. from breastfeeding, poses a serious toxicity risk. Since the toxicokinetic mechanisms that principally determine exposure outcomes undergo a significant developmental maturation, infants may respond to exposures in a different way than adults. Hence, suitable model systems are required to provide risk relevant information in pediatric populations. This dissertation’s primary goal was to provide a critical evaluation of two such model systems; first, a pharmacokinetic model that may predict an infant’s capacity to eliminate toxicants by cytochrome P-450 (CYP) mechanisms and second, the developing rat as a model of human CYP2E1 and CYP1A2 ontogeny.The first objective was to evaluate underlying assumptions of a pharmacokinetic model that describes the ontogeny of hepatic CYP activity using the rat. The study recognized some discrepancies with the stated assumptions. The impact of these discrepancies on the potential applicability of the model is discussed. As proof-of-concept, the observed data were fit to a model describing rat CYP2E1 and CYP1A2 ontogeny. A reasonable correlation (r = 0.75) was observed between observed and predicted oral clearance values of a CYP2E1 substrate indicating the potential applicability of such a model in risk assessment. The second objective was to conduct an extensive characterization of rat hepatic CYP2E1 and CYP1A2 ontogeny at mRNA, protein, activity and intrahepatic expression levels. The results were compared to available human data to determine the appropriateness of the rat for assessment of toxicokinetic mechanisms underlying age-dependent differences in susceptibility to toxicity. Similarities in age-dependent changes in mRNA, activity and zonal hepatic expression patterns were noted between the rat and human prior to weaning. Unlike human data, rats show good correlation between changes in CYP2E1 and CYP1A2 activity and transcript levels, but not with the immunoquantifiable protein. Recognizing such similarities and differences between rats and human regarding onset, rate and pattern of CYP ontogeny will improve the accuracy of rat-to-human extrapolation of developmental toxicokinetic data. Overall, the dissertation research provides mounting and supportive evidence for the use of such model systems in providing risk-relevant information in pediatric populations and to identify toxicokinetic mechanisms underlying age-dependent differences in susceptibility to toxicity

Integrative Student Learning: An Effective Team Learning Activity in a Learner-Centered Paradigm

Purpose: An Integrative Student Learning (ISL) activity was developed with the intent to enhance the dynamic of student teamwork and enhance student learning by fostering critical-thinking skills, self-directed learning skills, and active learning. Case Study: The ISL activity consists of three portions: teambuilding, teamwork, and a facilitator driven "closing the loop" feedback discussion. For teambuilding, a set of clue sheets or manufacturer's drug containers were distributed among student pairs who applied their pharmaceutical knowledge to identify two more student pairs with similar clues or drugs, thus building a team of six. For teamwork, each team completed online exams, composed of integrated pharmaceutical science questions with clinical correlates, using only selected online library resources. For the feedback discussion, facilitators evaluated student impressions, opened a discussion about the ISL activity, and provided feedback to teams' impressions and questions. This study describes three different ISL activities developed and implemented over three days with first year pharmacy students. Facilitators' interactions with students and three surveys indicated a majority of students preferred ISL over traditional team activities and over 90% agreed ISL activities promoted active learning, critical-thinking, self-directed learning, teamwork, and student confidence in online library searches. Conclusions: The ISL activity has proven to be an effective learning activity that promotes teamwork and integration of didactic pharmaceutical sciences to enhance student learning of didactic materials and confidence in searching online library resources. It was found that all of this can be accomplished in a short amount of class time with a very reasonable amount of preparation.   Type: Case Stud

Integrative Student Learning: An Effective Team Learning Activity in a Learner-Centered Paradigm

Purpose: An Integrative Student Learning (ISL) activity was developed with the intent to enhance the dynamic of student teamwork and enhance student learning by fostering critical-thinking skills, self-directed learning skills, and active learning. Case Study: The ISL activity consists of three portions: teambuilding, teamwork, and a facilitator driven “closing the loop” feedback discussion. For teambuilding, a set of clue sheets or manufacturer‘s drug containers were distributed among student pairs who applied their pharmaceutical knowledge to identify two more student pairs with similar clues or drugs, thus building a team of six. For teamwork, each team completed online exams, composed of integrated pharmaceutical science questions with clinical correlates, using only selected online library resources. For the feedback discussion, facilitators evaluated student impressions, opened a discussion about the ISL activity, and provided feedback to teams’ impressions and questions. This study describes three different ISL activities developed and implemented over three days with first year pharmacy students. Facilitators’ interactions with students and three surveys indicated a majority of students preferred ISL over traditional team activities and over 90% agreed ISL activities promoted active learning, critical-thinking, self-directed learning, teamwork, and student confidence in online library searches. Conclusions: The ISL activity has proven to be an effective learning activity that promotes teamwork and integration of didactic pharmaceutical sciences to enhance student learning of didactic materials and confidence in searching online library resources. It was found that all of this can be accomplished in a short amount of class time with a very reasonable amount of preparation

Attenuated Combined Action of Cyclosporine A and Hyperlipidemia on Atherogenesis in Rabbits by Thymoquinone

This descriptive study investigates in a rabbit model of atherosclerosis (i) the extent of atherogenesis induced by cyclosporine A (CsA) or hyperlipidemia alone or in combination and (ii) whether thymoquinone (TQ), a known herbal antioxidant, offers protection against these effects. New Zealand White female rabbits were assigned to five groups of six animals each: Group I, control; Group II, CsA [25 mg kg−1 day−1 orally (PO)]; Group III, 1% cholesterol; Group IV, 1% cholesterol + CsA (25 mg kg−1 day−1 PO); and Group V, 1% cholesterol + CsA (25 mg kg−1 day−1 PO) + TQ (10 mg kg−1 day−1 PO). Lipids and oxidative stress parameters [Malondialdehyde (MDA) and protein carbonyl] and aortic atherosclerosis were compared. CsA alone did not show a significant effect on either serum lipids and did not induce atherosclerosis. High-cholesterol diet induced atherosclerosis (45 ± 11% of the intimal surface of aorta was covered with atherosclerotic plaques). CsA and high-cholesterol diet increased atherosclerosis severity as measured from intimal and media lesions, but did not affect the extent of atherosclerosis. TQ decreased aortic MDA by 83%. It was also associated with reduced aortic atherosclerosis extend by 52% compared with Group IV. We concluded that (i) CsA aggravates hyperlipidemia-induced atherosclerosis and (ii) TQ attenuates the oxidative stress and atherogenesis induced by the combined effect of CsA and hyperlipidemia

Biosimilars: Review of regulatory, manufacturing, analytical aspects and beyond

Biologics have more complex production processes compared to small-molecule drugs. They may even prove labile when drifting from batch-to-batch or in different production locations. The development of new similar biological product was regulated early to face the relevant challenges of this industry. As a result, since 2006 biosimilars were introduced to biotechnology arena with a massive competition in pharmaceutical industry. In this review, the aspects related to similarity testing of biosimilars to the original biological products are discussed involving manufacturing challenges to ensure the quality, safety, and efficacy of these products to the patient health. Immunogenicity studies are highlighted as an important part of the safety assessments. Additionally, several analytical methods that are usually used to evaluate biosimilars in comparison to their reference biologic are summarized and categorized in terms of the intended physicochemical and biological characterization. On the other hand, the international efforts of several regulatory agencies including the European Medicines Agency, World Health Organization and United States Food and Drug Administration for biosimilar development are discussed according to updated revised guidelines

Natural Products; from the Laboratory to Clinical Practice

It has been such a great honor to serve as the Guest Editor for this Special Issue, “Exploration on Pharmacokinetics and Pharmacodynamics of Natural Molecules: Current Status and Future Perspectives” [...

The Modulation of Arachidonic Acid Metabolism and Blood Pressure-Lowering Effect of Honokiol in Spontaneously Hypertensive Rats

Background: Cardiovascular diseases have consistently been the leading cause of death in the United States over the last two decades, with 30% of the adult American population having hypertension. The metabolites of arachidonic acid (AA) in the kidney play an important role in blood pressure regulation. The present study investigates the antihypertensive effect of honokiol (HON), a naturally occurring polyphenol, and examines its correlation to the modulation of AA metabolism. Methods: Spontaneously hypertensive rats (SHR) were randomly divided into four groups. Treatment groups were administered HON intraperitoneally at concentrations of 5, 20, and 50 mg/kg. Blood pressure was monitored at seven-day intervals. After a total of 3 weeks of treatment, the rats were euthanized and the kidney tissues were collected to examine the activity of the two major enzymes involved in AA metabolism in the kidney, namely cytochrome P450 (CYP)4A and soluble epoxide hydrolase (sEH). Results: Rats treated with HON did not experience the rise in blood pressure observed in the untreated SHR. High-dose HON significantly reduced blood pressure and inhibited the activity and protein expression of the CYP4A enzyme in the rat kidney. The activity of the sEH enzyme in renal cytosol was significantly inhibited by medium and high doses of HON. Conclusion: Our data demonstrate the antihypertensive effect of HON and provide a novel mechanism for its underlying cardioprotective properties

Catechin Reduces Blood Pressure in Spontaneously Hypertensive Rats through Modulation of Arachidonic Acid Metabolism

(1) Background: hypertension affects approximately half of the adults in the United States (roughly 116 million). The cytochrome P450 (CYP)-mediated metabolism of arachidonic acid (AA) in the kidney has been found to play a major role in the pathogenesis of hypertension. This study examines the anti-hypertensive effect of the natural polyphenolic compound catechin (CAT) and investigates if it impacts the metabolism of AA in the kidney in comparison to captopril (CAP): a commonly used antihypertensive drug. (2) Methods: spontaneously hypertensive rats (SHR) were randomly divided into five groups. The treatment groups were administered CAT in drinking water at doses of 10 and 50 mg/kg. A positive control group received CAP at a dose of 10 mg/kg in the drinking water, and one group received both CAP and CAT at doses of 10 mg/kg and 50 mg/kg, respectively. Blood pressure was monitored weekly for five weeks. The activity of the two major enzymes involved in AA metabolism in the kidney, namely CYP4A and soluble epoxide hydrolase (sEH), were analyzed. (3) Results: CAP monotherapy was found to reduce blood pressure compared to the control untreated rats but did not demonstrate any effect on AA metabolism. Low- and high-dose CAT resisted the rise in blood pressure observed in the untreated SHR and significantly lowered blood pressure compared to the control group, respectively. Only rats treated with high CAT doses demonstrated significant inhibition of CYP4A and sEH enzyme activities. The coadministration of CAP and a high dose of CAT resulted in more pronounced blood pressure-lowering effects, but no more significant effects on AA metabolism were found compared to a high dose of CAT alone. (4) Conclusion: the modulation of AA metabolism in the kidney contributes, at least partially, to the blood pressure-lowering effect of CAT in SHR rats

An Organ System Approach to Explore the Antioxidative, Anti-Inflammatory, and Cytoprotective Actions of Resveratrol

Resveratrol is a phenolic phytochemical, with a stilbene backbone, derived from edible plants such as grape and peanut. It is a bioactive molecule with physiological effects on multiple organ systems. Its effects range from the neuroprotective to the nephroprotective, including cardiovascular, neuronal, and antineoplastic responses as a part of its broad spectrum of action. In this review, we examine the effects of resveratrol on the following organ systems: the central nervous system, including neurological pathology such as Parkinson’s and Alzheimer’s disease; the cardiovascular system, including disorders such as atherosclerosis, ischemia-reperfusion injury, and cardiomyocyte hypertrophy; the kidneys, including primary and secondary nephropathies and nephrolithiasis; multiple forms of cancer; and metabolic syndromes including diabetes. We emphasize commonalities in extracellular matrix protein alterations and intracellular signal transduction system induction following resveratrol treatment. We summarize the known anti-inflammatory, antioxidative, and cytoprotective effects of resveratrol across disparate organ systems. Additionally, we analyze the available literature regarding the pharmacokinetics of resveratrol formulations used in these studies. Finally, we critically examine select clinical trials documenting a lack of effect following resveratrol treatment