bluuebunny/crossref_metadata_2025 huggingface dataset:
Carnitine and Sepsis: A Review of an Old Clinical Dilemma
Authors: Hatamkhani Shima , Karimzadeh Iman , Elyasi Sepideh , Farsaie Shadi , Khalili Hossein
Published: March 2016

Purpose. The precise role of carnitine as the key regulator of lipid metabolism in sepsis is unclear. In this review, available experimental as well as clinical evidences regarding the probable beneficial effects of carnitine in sepsis were evaluated. Method. A comprehensive literature search was performed in the related medical databases. Related experimental and clinical studies were included. Results and Conclusion: The plasma and tissue level of carnitine or its derivatives in septic condition is variable and inconclusive. Survival and outcomes are considered in only few studies. Despite its favorable safety profile, due to limited clinical evidence, it seems reasonable not to currently consider carnitine as a mandatory and beneficial supplement under septic conditions. Further well-designed, standard clinical trials are warranted in this regards.

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Nanosponges: A Novel Class of Drug Delivery System - Review
Authors: S Selvamuthukumar , S Anandam , Krishnamoorthy Kannan , Rajappan Manavalan
Published: March 2016

ABSTRACT - Effective targeted drug delivery systems have been a dream for a long time, but it has been largely frustrated by the complex chemistry that is involved in the development of new systems. The invention of nanosponges has become a significant step toward overcoming these problems. Nanosponges are tiny sponges with a size of about a virus, which can be filled with a wide variety of drugs. These tiny sponges can circulate around the body until they encounter the specific target site and stick on the surface and begin to release the drug in a controlled and predictable manner. Because the drug can be released at the specific target site instead of circulating throughout the body it will be more effective for a particular given dosage. Another important character of these sponges is their aqueous solubility; this allows the use of these systems effectively for drugs with poor solubility.

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HPMC Capsules: Current Status and Future Prospects
Authors: Al-Tabakha Moawia M
Published: March 2016

Hydroxypropyl methylcellulose (HPMC) is employed for a wide variety of pharmaceutical and food preparations. Its applications as viscolizing agent (thickening agent), coating polymer, bioadhesive, in solid dispersion to enhance solubility, binder in the process of granulation and in modified release formulations have been well documented. One other notable use is in the production of capsule shells, replacing the animal derived gelatin in conventional two-piece capsules. The aim of this review is to systemically survey published literature on the HPMC use in capsule shells and resolve questions regarding their suitability as a replacement for hard gelatin capsules. Future refinements in the production and filling of HPMC capsule shells and improvement in their in vivo/in vitro dissolution would ensure their superiority over hard gelatin capsules.
Literature Values of Terminal Half-Lives of Clozapine are Dependent on the Time of the Last Data Point
Authors: Fang Jim , Mosier Karen
Published: March 2016

The pharmacokinetics of clozapine is a subject of intensive research because of its narrow therapeutic window and susceptibility to drug-drug interactions. A systematic literature search was conducted in PubMed and Google Scholar for half-life values of clozapine in humans. Twenty-one publications were found to contain terminal half-life information of clozapine in humans along with the time of the last plasma sample. Average values of the terminal half-lives of clozapine were calculated to be 10.2, 13.2, 14.2, 18.3 and 29.2 hours with a last data point at 12, 24, 48, 72 and 120 hours, respectively. This confirms the notion that one would arrive at longer terminal half-lives when longer blood sampling times are used in pharmacokinetic studies on clozapine. “Terminal half-lives” of therapeutic agent are routinely computed and reported in literature. For drugs with a third deep compartment such as clozapine, one should remember to consider the time of the last data point when comparing the “terminal” half-life.
Association of Angiotensinogen (M235T) Gene Polymorphism with Blood Pressure Lowering Response to Angiotensin Converting Enzyme Inhibitor (Enalapril)
Authors: Srivastava Kamna , Chandra Sudhir , Bhatia Jagriti , Narang Rajiv , Saluja Daman
Published: March 2016

Purpose: It has been suggested that genetic backgrounds, which have an association with essential hypertension, may also determine the responsiveness to ACE inhibitor. We determined the association of angiotensinogen (M235T) gene polymorphism with essential hypertension and the relationship between polymorphism in the angiotensinogen (M235T) gene and blood pressure response to ACE inhibitor (Enalapril) in patients with essential hypertension from northern Indian subjects. Methods: 250 patients with essential hypertension and 250 normal healthy controls from Delhi and surrounding areas were recruited for the investigation. Blood pressure was recorded before and after 6 weeks of treatment with ACE inhibitors, Enalapril. Genotyping were carried out by polymerase chain reaction and Restriction fragment length polymorphism technique. Results: Statistically significant association of T allele was observed with essential hypertension [x2 = 14.67, p = 0.00013, Odds ratio = 1.76 (1.3-2.32) at 95% CI], the relative risk at 95% CI being 1.28 (1.2-1.54). The decrease in systolic blood pressure and diastolic blood pressure after six weeks of treatment of the patients carrying TT genotype (SBP = 26±17.4 mmHg, DBP = 14.83±7.6mmHg) were greater than the groups carrying MT (SBP = 3.0±7.8 mmHg, DBP =6.2±3.0 mmHg) and MM genotypes (SBP = 1.2±0.8 mmHg, DBP = 0.10±12.1 mm Hg. Conclusions: The angiotensinogen (M235T) gene polymorphism is significantly associated with essential hypertension. Patients carrying TT genotype had higher blood pressure lowering response when treated with ACE inhibitor, Enalapril than those carrying MM and MT genotypes suggesting that the T allele may be a possible genetic marker for essential hypertension.

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Alteration of Pharmacokinetics of Grepafloxacin in Type 2 Diabetic Rats
Authors: Watanabe Meguho , Kobayashi Masaki , Ogura Jiro , Takahashi Natsuko , Yamaguchi Hiroaki , Iseki Ken
Published: March 2016

Purpose. Patients with type 2 diabetes are generally treated with various pharmacological compounds and are exposed to a high risk of drug-drug interactions. However, alterations of pharmacokinetics in a type 2 diabetes model have been obscure. The present study was undertaken to investigate the effects of type 2 diabetes on the pharmacokinetics of the fluoroquinolone grepafloxacin (GPFX) and the expression level of P-glycoprotein (P-gp), one of the drug efflux transporters. Methods. We used Goto-Kakizaki (GK) rats, a lean model of type 2 diabetes. Plasma concentration and intestinal, renal, and biliary clearance of GPFX were measured after intravenous and intraintestinal administration in Wistar and GK rats. Real-time PCR and Western blotting were used to assess mRNA and protein expression levels. Results. We found a significant increase in the plasma concentrations of GPFX at 90, 120 and 240 minutes after intraintestinal administration in GK rats compared with the concentrations in Wistar rats but not after intravenous administration. The increase in plasma GPFX concentration was associated with reduction in jejunal clearance of GPFX caused by a decrease in secretory transport of GPFX. However, there was no correlation between the decrease in secretory transport of GPFX and P-gp expression level. Conclusion. Type 2 diabetic conditions alter P-gp function as well as expression level and correlate poorly with each other. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Efficacy and Safety of Platelet Inhibitors
Authors: Binazon Ornella , Dubois-Gauche Audrey , Nanau Radu M , Neuman Manuela G
Published: March 2016

Ischemic heart disease is the second leading cause of death in the world. The proportion of deaths resulting from this condition has decreased in the last two decades, mainly as a result of improved primary and secondary prevention of cardiovascular events, as well as the development of patient awareness and medical and pharmacological management. The purpose of the present review is to analyze pathophysiological events leading to platelet involvement in cardiovascular thrombosis, as well as the role of pharmacogenetics in modulating the risk of cardiovascular disorders. The present work was performed using a PubMed search with combinations of key words relevant to the subject in both English and French. In addition to the pharmacokinetic and pharmacodynamic characteristics of platelet inhibitors, this work reviews the efficacy and adverse events observed during the clinical trials with these drugs. This review further summarizes possible therapeutic drug monitoring strategies for antiplatelet drugs. The novelty of this work is the description of the lymphocyte toxicity assay as a specific method of diagnosing and predicting possible idiosyncratic adverse events attributable to antiplatelet medication.

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Effects of In Vivo Hepatic Ischemia-Reperfusion Injury on the Hepatobiliary Disposition of Rhodamine 123 and its Metabolites in Isolated Perfused Rat Livers
Authors: Parasrampuria Ridhi , Shaik Imam H. , Mehvar Reza
Published: March 2016

Purpose. A few studies have shown that normothermic hepatic ischemia-reperfusion (IR) injury may affect the mRNA and/or protein levels of canalicular transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2). However, the effects of the injury on the functions of these canalicular transporters with respect to the biliary excretion of drugs remain largely unknown. Therefore, the purpose of this study was to investigate the effects of warm hepatic IR on the hepatobiliary disposition of rhodamine 123 (RH-123), a P-gp substrate, and its glucuronidated metabolite (RH-Glu), an Mrp2 substrate, in rats. Methods. Twenty four or 72 h following a 60-min partial ischemia or sham operation in rats, livers were isolated and perfused ex vivo with a constant concentration (~100 ng/mL) of RH-123. The concentration of RH-123 and its glucuronidated (RH-Glu) and deacylated (RH-110) metabolites were determined in the outlet perfusate, bile, and the liver tissue using HPLC, and relevant pharmacokinetic parameters were estimated. Results. Twenty-four-h IR caused a significant reduction in the hepatic extraction ratio of RH-123 (IR: 0.857 ± 0.078; Sham: 0.980 ± 0.017) and the biliary recovery of the parent drug and RH-Glu by 43% and 44%, respectively. The reductions in the biliary recovery were associated with significant reductions in the apparent biliary clearance of RH-123 and RH-Glu. Mass balance data showed that the formation of the glucuronidated or deacylated metabolite was not significantly affected by the 24-h IR injury. In contrast to the 24-h IR, the injury did not have any effect on the hepatobiliary disposition of RH-123 or its metabolites following 72 h of reperfusion. Conclusions. It is concluded that the pharmacokinetics of drugs that are subject to biliary excretion by the canalicular P-gp and Mrp2 transporters may be altered shortly after hepatic IR injury.

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Characterization Of Selective TRPM8 Ligands And Their Structure Activity Response (S.A.R) Relationship
Authors: Sherkheli Muhammad Azhar , Vogt-Eisele Angela K. , Bura Daniel , Beltrán Márques Leopoldo R. , Gisselmann Günter , Hatt Hanns
Published: March 2016

PURPOSE: Transient receptor potential melastatin-8 (TRPM8) is an ion channel expressed extensively in sensory nerves, human prostate and overexpressed in a variety of cancers including prostate, breast, lung, colon and skin melanomas. It is activated by innoxious cooling and chemical stimuli. TRPM8 activation by cooling or chemical agonists is reported to induce profound analgesia in neuropathic pain conditions. Known TRPM8 agonists like menthol and icilin cross-activate other thermo-TRP channels like TRPV3 and TRPA1 and mutually inhibit TRPM8. This limits the usefulness of menthol and icilin as TRPM8 ligands. Consequently, the identification of selective and potent ligands for TRPM8 is of high relevance both in basic research and for therapeutic applications. In the present investigation, a group of menthol derivates was characterized. These ligands are selective and potent agonists of TRPM8. Interestingly they do not activate other thermo-TRPs like TRPA1, TRPV1, TRPV2, TRPV3 and TRPV4. These ion channels are also nociceptors and target of many inflammatory mediators.

METHODS: Investigations were performed in a recombinant system: Xenopus oocytes microinjected with cRNA of gene of interest were superfused with the test substances after initial responses of known standard agonists. Evoked currents were measured by two-electrode voltage clamp technique.

RESULTS: The newly characterized ligands possess an up to six-fold higher potency (EC50 in low µM) and an up to two-fold increase in efficacy compared to the parent compound menthol. In addition, it is found that chemical derivatives of menthol like CPS-368, CPS-369, CPS-125, WS-5 and WS-12 are the most selective ligands for TRPM8. The enhanced activity and selectivity seems to be conferred by hexacyclic ring structure present in all ligands as substances like WS-23 which lack this functional group activate TRPM8 with much lower potency (EC50 in mM) and those with pentacyclcic ring structure (furanone compounds) are totally inactive.

CONCLUSION: The new substances activate TRPM8 with a higher potency, efficacy and specificity than menthol and will thus be of importance for the development of pharmacological agents suitable for treatment and diagnosis of certain cancers and as analgesics.

STATEMENT OF NOVELTY: The new compounds have an unmatched specificity for TRPM8 ion channels with additional display of high potency and efficacy. Thus these substances are better pharmacological tools for TRPM8 characterization then known compounds and it is suggested that these menthol-derivates may serve as model substances for the development of TRPM8 ligands.
Intranasal Drug Delivery: How, Why and What for?
Authors: Pires Anaísa , Fortuna Ana , Alves Gilberto , Falcão Amílcar
Published: March 2016

Over the last decade the interest in intranasal delivery as a non-invasive route for drug administration has been exponentially increased. Since the nasal mucosa offers numerous benefits as a target issue for drug delivery, a wide variety of therapeutic compounds may be administered intranasally for topic, systemic and central nervous system action. The present paper reviews the relevant aspects of nasal anatomy, physiology and histology, and refers to the biological, physicochemical and pharmaceutical factors that must be considered during the process of discovery and development of nasal drugs as well as in their incorporation in appropriate nasal pharmaceutical formulations.
Bioequivalence assessment of topical clobetasol propionate products using visual and chromametric assessment of skin blanching
Authors: Au Wai Ling , Skinner Michael , Kanfer Isadore
Published: March 2016

ABSTRACT - PURPOSE: The assessment of the degree of skin blanching following the application of a formulation containing a topical corticosteroid has been established as a surrogate method for the determination of bioequivalence of such topical preparations. Whereas initially the procedure involved visual assessment of the blanching response, an instrumental procedure using a chromameter was subsequently recommended as the method of choice in such evaluations. In this study, both visual and chromametric assessments have been carried out on two topical creams containing clobetasol propionate (0.05%) and the results from both methods are compared and discussed. METHODS: Human subjects (volunteers) were subjected to screening using a cream containing 0.05% clobetasol propionate, in order to identify appropriate subjects for inclusion in the study. Subsequently the study was implemented according to the FDA guidance using both visual and chromameter assessment techniques. Blanching responses were assessed visually by three trained, independent observers and instrumentally using a Chromameter. An ED50 of 36 min was used as the dose duration based upon data previously obtained from a pilot study using the same topical corticosteroid reference product. A visual rating scale of 0-4 and the a-scale readings from the chromameter were used. RESULTS: The visual and chromameter blanching profiles showed similar blanching responses and corresponded well with each other. The 90% confidence interval for the visual and chromameter data were calculated using Lock's method and when only the data obtained from 23 subjects who were identified as "detectors" (according to the FDA guidance) were used, the products fell within the bioequivalence acceptance range of 80-125% using the visual assessment method (99.3-111.6%) whereas the data using a chromameter (86.5-129.3%) were just outside the acceptance limits. However, when all subjects (n=34) were included in the calculations, both the visual (97.9-109.2) and chromameter (90.2-120.7) data fell within the acceptance range for the declaration of bioequivalence.CONCLUSIONS: Whereas visual data indicated bioequivalence using either data from "detectors" or data from all subjects, the chromameter data from "detectors" only indicated bioinequivalence but inclusion of all subject data fell within the acceptance range to be declared bioequivalent.
Interactions between Phytochemical Components of Sutherlandia Frutescens and the Antiretroviral, Atazanavir In Vitro: Implications for Absorption and Metabolism
Authors: Müller Adrienne C , Patnala Srinivas , Kis Olena , Bendayan Reina , Kanfer Isadore
Published: March 2016

Purpose. African traditional medicinal plants, such as Sutherlandia frutescens have the potential to interact pharmacokinetically with the protease inhibitor class of antiretrovirals, thereby impacting on their safety and efficacy. The effects of extracts and phytochemical components of Sutherlandia frutescens, on the in vitro absorption and metabolism of the protease inhibitor, atazanavir were thus investigated. Methods. Aqueous and methanolic extracts of Sutherlandia frutescens were prepared by freeze-drying of hot water and methanol decoctions of Sutherlandia frutescens plant material respectively, whilst crude triterpenoid glycoside and flavonol glycoside fractions were isolated by solvent extraction and subsequent column chromatography. Atazanavir was quantitated in the absence or presence of these compounds as well as commercially available purported constituents of Sutherlandia frutescens, namely, L-canavanine, L-GABA and D-pinitol, after a one hour co-incubation in Caco-2 cell monolayers and human liver microsomes. Results. The triterpenoid and flavonol glycoside fractions were found to be present in the aqueous and methanolic extracts of Sutherlandia frutescens and were shown to contain the sutherlandiosides and sutherlandins known to be present in Sutherlandia frutescens. The aqueous extract and D-pinitol significantly reduced atazanavir accumulation by Caco-2 cells, implying a decrease in atazanavir absorption, whilst the opposite was true for the triterpenoid glycoside fraction. Both the aqueous and methanolic extracts inhibited atazanavir metabolism in human liver microsomes, whilst enhanced atazanavir metabolism was exhibited by the triterpenoid glycoside fraction. Conclusions. The extracts and phytochemical components of Sutherlandia frutescens influenced the accumulation of atazanavir by Caco-2 cells and also affected ATV metabolism in human liver microsomes. These interactions may have important implications on the absorption and metabolism and thus the overall oral bioavailability of atazanavir.

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The Role of SIRT3 in Mediating Cardioprotective Effects of RAS Inhibition on Cardiac Ischemia-Reperfusion
Authors: Javadov Sabzali , Escobales Nelson
Published: March 2016

Cardiac ischemia-reperfusion stimulates the renin-angiotensin system (RAS) associated with elevated levels of circulating angiotensin II. Numerous studies demonstrate that the antagonist for the angiotensin II type 1 receptor, losartan improves cardiac function in animal models of ischemia-reperfusion. Molecular mechanisms of the cardioprotective effects of RAS inhibitors on cardiac ischemia-reperfusion remain poorly understood, and are not associated with the anti-hypertensive action of these drugs. This Commentary focuses on the study published in the Journal of Pharmacy and Pharmaceutical Sciences, 2015, 18:112-123, that elucidates the role of SIRT3 in the cardioprotective action of losartan against ischemic-reperfusion injury. We provide comprehensive discussion of the role of mitochondria in the cardioprotective effects of losartan through SIRT3. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Safety Assessment of Potentially Inappropriate Medications Use in Older People and the Factors Associated with Hospital Admission
Authors: Varallo Fabiana Rossi , Capucho Helaine Carneiro , Planeta Cleópatra Silva , Mastroianni Patrícia De Carvalho
Published: March 2016

Purpose: Potentially Inappropriate Medications (PIM) use in elderly people may be responsible for the development of Adverse Drug Reaction (ADR) which, when severe, leads to hospital admissions. Objectives: to estimate the prevalence of elderly who had used PIM before being admitted to hospital admission and to identify the risk factors and the hospitalizations related to ADR arising from PIM. Methods: A descriptive and cross-sectional study was performed in the internal medicine ward of a teaching hospital (Brazil), in 2008. With the aid of a validated form, patients aged ≥ 60 years, with length of hospital stay ≥ 24 hours, were interviewed about drugs taken prior to the hospital admission and the complaints/reasons for hospitalization. Results: 19.1% (59/308) of older patients had taken PIM before hospital admission and in 4.9%; there were a causal relation between the PIM taken and the complaint reported. PIM responsible for admissions were: amiodarone, amitriptyline, cimetidine, clonidine, diazepam, digoxin, estrogen, fluoxetine, lorazepam, short-acting nifedipine and propranolol. 47.0% of the clinical manifestations of PIM-related ADR were: dizziness, fatigue, digoxin toxicity and erythema. Only polypharmacy was detected as a risk factor for the occurrence of ADR of PIM (p = 0.02). Conclusion: PIM use in elderly people is not a risk factor for ADR-related hospital admission. Probably, severe ADR, which lead to hospitalizations of older people, can be explained by idiosyncratic response or the predisposition of these patients to develop adverse drug events, whether or not drugs are classed as PIM.

Key-words: potentially inappropriate medication (PIM), older people, adverse drug reaction (ADR), hospital admission, pharmacovigilance
Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier
Authors: Kaur Manjit , Badhan Raj Kumar Singh
Published: March 2016

PURPOSE: Breast cancer resistance protein (BCRP/ABCG2) is a drug efflux transporter expressed at the blood cerebrospinal fluid barrier (BCSFB), and influences distribution of drugs into the central nervous systems (CNS). Current inhibitors have failed clinically due to neurotoxicity. Novel approaches are needed to identify new modulators to enhance CNS delivery. This study examines 18 compounds (mainly phytoestrogens) as modulators of the expression/function of BCRP in an in vitro rat choroid plexus BCSFB model.   METHODS:  Modulators were initially subject to cytotoxicity (MTT) assessment to determine optimal non-toxic concentrations. Reverse-transcriptase PCR and confocal microscopy were used to identify the presence of BCRP in Z310 cells. Thereafter modulation of the intracellular accumulation of the fluorescent BCRP probe substrate Hoechst 33342 (H33342), changes in protein expression of BCRP (western blotting) and the functional activity of BCRP (membrane insert model) were assessed under modulator exposure. RESULTS: A 24 hour cytotoxicity assay (0.001 µM-1000 µM) demonstrated the majority of modulators possessed a cellular viability IC50 > 148 µM. Intracellular accumulation of H33342 was significantly increased in the presence of the known BCRP inhibitor Ko143 and, following a 24 hour pre-incubation, all modulators demonstrated statistically significant increases in H33342 accumulation (P < 0.001), when compared to control and Ko143. After a 24 hour pre-incubation with modulators alone, a 0.16-2.5 -fold change in BCRP expression was observed for test compounds. The functional consequences of this were confirmed in a permeable insert model of the BCSFB which demonstrated that 17-β-estradiol, naringin and silymarin (down-regulators) and baicalin (up-regulator) can modulate BCRP-mediated transport function at the BCSFB. CONCLUSION: We have successfully confirmed the gene and protein expression of BCRP in Z310 cells and demonstrated the potential for phytoestrogen modulators to influence the functionality of BCRP at the BCSFB and thereby potentially allowing manipulation of CNS drug disposition. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Antimicrobial and P450 Inhibitory Properties of Common Functional Foods
Authors: Nguyen San , Huang Huang , Foster Brian C , Tam Teresa W , Xing Tim , Smith Myron L , Arnason John T , Akhtar Humayoun
Published: March 2016

PURPOSE:  To study the effect of functional foods on human cytochrome P450 (CYP) and the gut bacterial microflora that may potentially affect drug metabolism and ultimately affect human health and wellness. METHODS: This study examined a variety of food plants from the Apiaceae, Fabaceae, and Lamiaceae families for their inhibitory potential on cytochrome 2D6-, 3A4-, 3A5-, and 3A7-mediated metabolism. The antimicrobial effects of these samples were also investigated with 7 selected bacterial surrogate species to determine potential effects on the gut microflora. RESULTS: The highest CYP inhibitory activities, based upon visual examination, were observed from extracts of celery seed, cumin, fennel seed, basil, oregano, and rosemary belonging to the Apiaceae and Lamiaceae families, respectively. Likewise, the strongest antimicrobial activities were also observed in the Apiaceae and Lamiaceae. No significant antimicrobial and CYP inhibition was observed in the Fabaceae extracts. CONCLUSION: Results demonstrated the possible risk of food-drug interactions from spice and herb plants may affect drug disposition and safety. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Review of the cosolvency models for predicting solubility of drugs in water-cosolvent mixtures
Authors: Jouyban Abolghasem
Published: March 2016

The cosolvency models presented from 1960 to 2007 were reviewed and their accuracies for correlating and/or predicting the solubility of drugs in water-cosolvent mixtures were discussed. The cosolvency models could be divided into theoretical, semi-empirical and empirical models, the first group of models provide basic information from the solution, while the last group of models are good suitable for solubility correlation studies. The simplest cosolvency model, i.e. the log-linear model of Yalkowsky, provides an estimate of drug solubility in water-cosolvent mixtures using aqueous solubility of the drug, whereas the Jouyban-Acree model predicts the solubility with an acceptable error with the cost of one more data point (the solubility in neat cosolvent) which is required as input value in the prediction process. A number of error terms used in the literature was also discussed with a brief comments on the acceptable prediction error for pharmaceutical applications.
Pathogenesis of Pregabalin-Induced Limb Defects in Mouse Embryos
Authors: Etemad Leila , Jafarian Amir Hossein , Moallem Seyed Adel
Published: March 2016

Purpose: It is known that antiepileptic drugs might adversely affect neuronal function and thus influence brain development. However, we have reported that limb deformities are one of the most prominent disturbances caused by pregabalin (PGB) in the developing embryo. The aim of this work is to gain a better understanding of possible molecular mechanisms behind the musculoskeletal injuries and limb deformities associated with PGB. Methods: Pregnant mice divided into four groups. Each mouse received an intraperitoneal injection (IP) of 0, 20 (group I), 40 (group II) or 80 (group III) mg/kg/day of PGB during the organogenesis period. On gestational day 18, embryos were separated and their limbs were dissected. Levels of apoptotic proteins were analyzed by Western blotting. To establish whether apoptosis is present in the limbs, the specimens were examined by TUNEL. Pathological findings were also reported as a score ranging from 1 to 3 based on the level of differentiation. Results: Western blot analysis demonstrated that PGB in all PGB-treated groups significantly upregulated the levels of cleaved caspase-3, 8 and 9. Also, the results showed that PGB exposure increased the percentage of TUNEL positive cells in different limb tissues especially the mesenchymal tissue. The histopathological findings revealed that PGB administration to pregnant mice inhibited limb tissue differentiation, albeit to varying degrees. Conclusions: The result of our study revealed that apoptosis and inhibition of limb tissue differentiation play an important role in the pathogenesis of PGB-induced limb malformations. Both intrinsic and extrinsic caspase-dependent pathways of cell death are important in mediating the abnormal limb development triggered by insult with the PGB. Evaluating the effect of PGB on molecules involved in the cross-talk between intrinsic and extrinsic apoptotic pathways and cell adhesion, migration, proliferation, and differentiation during embryonic development can further help to identify and clarify the involved mechanisms.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Poly[N-(2-aminoethyl)ethyleneimine] as a New Non-Viral Gene Delivery Carrier: The Effect of Two Protonatable Nitrogens in the Monomer Unit on Gene Delivery Efficiency
Authors: Khazaie Yahya , Dorkoosh Farid Abedin , Novo Luis , Gaal Ethlinn Van , Fassihi Afshin , Mirahmadi-Zareh Seyedeh Zohreh , Esfahani Mohammad Hossein Nasr , Van Nostrum Cornelus F. , Hennink Wim E.
Published: March 2016

Purpose. The aim of this study was to investigate the in vitro gene delivery efficiency of poly[N-(2-aminoethyl)ethylene-imine](PAEEI), a polymer with a linear Polyethyleneimine (LPEI) backbone and with aminoethyl side groups that has two protonatable nitrogen atoms per monomer unit instead of one as in LPEI (an established gene delivery polymer). Method. PAEEI (Mn=4.5 kDa, Mw= 10 kDa) was synthesized by ring-opening polymerization of N-(2-(1’-aziridino)ethyl)formamide followed by hydrolysis of the amide groups.  The buffering capacity of the resulting polymer was determined by acid-base titration and consequently the percentage of the protonated nitrogen atoms was calculated. Polyplexes were prepared separately in buffers with different ionic strength including Hepes buffered saline (150 mM NaCl) and Hepes buffered glucose (5% glucose) and their zeta-potential, hydrodynamic diameter and colloidal stability were measured. Transfection activity (and toxicity in Hela cells) of the polyplexes were done in HeLa, CHO and HEK293T cells. Cell incubations with polyplexes were done both in the presence and absence (HeLa cells) of serum. Results. PAEEEI showed two times more buffering capacity than LPEI. PAEEI-based Polyplexes had about the same size and zeta-potential as those of LPEI, with a higher colloidal stability in saline buffer in continuous particle size measurement. Their transfection activity was slightly higher than 22-kDa LPEI polyplexes whereas their toxicity profiles were similar in cell lines studied. The PAEEI polyplexes showed gene expression activity both in the presence and absence of serum. Conclusion. Paying attention to the fact that LPEI molecules with smaller sizes than 22 kDa  show less transfection efficiency than LPEI 22, the effect of smaller size of PAEEI (10 kDa) on the gene delivery efficiency was compensated by its higher buffering capacity due to carrying more protonatable nitrogen per monomeric unit comparing with LPEI (22 kDa). Having slightly higher transfection efficiency and better colloidal stability than PEI-based systems, PAEEI is an attractive candidate for future in vivo gene delivery studies.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
The Impact of Implementation of the Canadian Regulatory Requirements on the Quality of Natural Health Products: The Glucosamine Case
Authors: Aghazadeh-Habashi Ali , Duke John , Jamali Fakhreddin
Published: March 2016

ABSTRACT – Purpose. We investigated whether the recent implementation of the regulatory requirements for the entry to the Canadian market of natural products has resulted in improved quality of the available glucosamine products. Methods. Eleven available products, of which 8 had been tested in 2002 (7 had contained substantially lower than the label claim of the active ingredient), and a European pharmaceutical grade tablet were assayed for their glucosamine content. The potassium and sodium contents of the products were also tested. Results. Nine of the 11 Canadian products and the European tablet had more than 91% of the label claim of the active ingredient, hence, met the criterion. Two products contained 71 and 78% label claim. The electrolyte contents were very variable but constituted only a small fraction of the daily requirements. Conclusion. Most tested glucosamine products passed the Health Canada requirements. This improvement is likely due to the publicity regarding the low quality of the products in the past and also a result, at least in part, of the introduction of the new regulatory requirements.  The sub-standard quality of a few tested products is still of concern.This  article  is  open  to  POST-PUBLICATION  REVIEW.  Registered  readers  (see  “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
A Rapid and Sensitive HPLC Method for Quantitation of Paclitaxel in Biological Samples using Liquid-Liquid Extraction and UV Detection: Application to Pharmacokinetics and Tissues Distribution Study of Paclitaxel Loaded Targeted Polymeric Micelles in.....
Authors: Rezazadeh Mahboubeh , Emami Jaber , Mostafavi Abolfazl , Rostami Mahboubeh , Hassanzadeh Farshid , Sadeghi Hojjat , Minaiyan Mohsen , Lavasanifar Afsaneh
Published: March 2016

A simple, rapid, and sensitive reversed-phase HPLC method was developed and validated for determination of paclitaxel (PTX) in plasma, various organs and tumor tissues of tumor-bearing mice. Tissue specimens of liver, kidneys, spleen, lungs, heart and tumor were separately homogenized in normal saline. Plasma or tissue homogenate (250 µl) containing PTX and internal standard (diazepam) were extracted by diethyl ether (6 ml). The separation was achieved on a µ-Bondapak C18 HPLC column using sodium acetate buffer solution (0.01 M)/acetonitrile (58/42 v/v) at pH 5 ± 0.1 and flow rate of 1.9 mL/min. The effluent was monitored at 227 nm and column temperature was adjusted at 58ºC. The internal standard and PTX were eluted at 4.2 and 5.2 min, respectively and no interfering peaks were observed.  Calibration curves were linear over the concentration range of 0.25-10 µg/ml of PTX in plasma and 0.3-20 µg/ml PTX in tissue homogenates with acceptable precision and accuracy (<15%).  The mean recoveries of the drug after plasma extraction was 87.4% ± 3.6 while those of tissue homogenates ranged from 62.1± 4.5 to 75.5± 3.2 depending on the type of tissues studied.  PTX was stable in samples with no evidence of degradation during 3 freeze–thaw cycles and 3 months storage at −70 °C.  The developed HPLC method was applied to quantify PTX in the mouse plasma and tissues after intravenous administration of 10 mg equivalent PTX/Kg dose of PTX-loaded tocopherol succinate-chitosan-polyethylene glycol-folate (TS-CS-PEG-FA) micelles formulation or Anzatax® (Cremophor® EL- based formulation of PTX) to female Balb/c mice. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Pharmacokinetic of Diclofenac in the Presence and Absence of Glibenclamide in the Rat
Authors: León-Reyes María R. , Castañeda-Hernández Gilberto , Ortiz Mario I
Published: March 2016

ABSTRACT - PURPOSE. There is evidence that the sulfonylurea antidiabetic agent glibenclamide reduces the analgesic action of non-steroidal anti-inflammatory drugs (NSAIDs), opioids and neuromodulators in animal models. Therefore, in view of the vast clinical uses and interactions of NSAIDs with commonly used therapeutic agents, the interaction of the NSAID diclofenac and glibenclamide was investigated about pharmacokinetic profile and antinociceptive effect in rats. METHODS. Antinociception was assessed using the formalin test. Fifty microliters of diluted formalin was injected s.c. into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection. Rats were treated with oral administration of vehicle or increasing doses of diclofenac (3-18 mg/kg) before formalin injection. To determine the pharmacodynamic interaction between diclofenac and glibenclamide, the effect of oral administration of glibenclamide (1-30 mg/kg) on the antinociceptive effect induced by diclofenac (18 mg/kg, p.o.) was assessed. To evaluate the pharmacokinetic interaction between diclofenac and glibenclamide, the effect of glibenclamide (10 mg/kg, p.o.) on the pharmacokinetic of diclofenac (18 mg/kg, p.o.) was studied in the rat. Blood samples were taken over 8 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of diclofenac. Pharmacokinetic parameters were estimated using noncompartmental analysis. RESULTS. Systemic administration of diclofenac produced a dose-dependent antinociceptive effect in the formalin test. Systemic treatment with glibenclamide prevented diclofenac-induced antinociception. In pharmacokinetic interaction study, no significant (P>0.05) change in diclofenac concentration-time profiles in the presence of glibenclamide was detected. CONCLUSION. The experimental findings suggest that systemic glibenclamide is able to block the diclofenac-induced antinociception in the rat formalin test. Besides, this antagonism was not produced by diminution in the bioavailability of diclofenac. Likewise, the validated assay had sufficient accuracy and precision for pharmacokinetic determination of diclofenac in the rat.
The Antiinflammatory Action and Pharmacokinetics of a Novel Glucosamine-based Di-Peptide Aminosugar
Authors: Gilzad-Kohan Mohammad H. , Kaur Kamaljit , Jamali Fakhreddin
Published: March 2016

Purpose. We have previously shown favorable in vitro gut permeability for three novel di-peptide esters of glucosamine (GlcN) likely facilitated by the peptide transporter 1 (PepT1). Herein, we report the development of a novel assay for the determination of bioavailability of the peptide ester of interest, the anti-inflammatory properties of a glycine-valine ester derivative of GlcN (GVG) as well as its pharmacokinetics under healthy and inflammatory conditions. Methods. A pre-column derivatization (with 9-fluorenylmethoxycarbonyl) HPLC assay was developed to study bioavailability of GVG, GlcN or cleaved GlcN in the rats that were cannulated in their right jugular vein for blood collection. The compounds of interest were orally administered to both healthy and arthritic rats. Serial blood samples and urine were collected and assayed for the compounds. The stability of the GVG was also tested after incubation with the rat feces. Efficacy of GVG was tested in inflamed rats (injection of 0.2 mL of Mycobacterium butyricum in squalene) following GVG (20 and 30 mg/kg/day GlcN equivalent) or GlcN (20 and 90 mg/kg/day) administration. Arthritis index was calculated at the end of the experiment. Results. The assay was linear (ranged between 0.05-20 μg/mL) and reproducible (intra- and inter-day<10%). Among the tested compounds, only GVG showed a significantly higher plasma concentrations and urinary excretion than GlcN (≈3-fold increase). GVG showed a favorable stability in the rat feces. Adjuvant arthritis was completely prevented with doses greater than 20 mg/kg/day with GVG being 3-fold more potent than GlcN. Conclusion. The examined glycine-valine-GlcN di-peptide aminosugar is a potent anti-inflammatory compound due to its favorable properties to deliver GlcN into the systemic circulation. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Melatonin Interaction Resulting in Severe Sedation
Authors: Foster Brian C , Cvijovic Kosta , Boon Heather S , Tam Teresa W , Liu Rui , Murty Mano , Vu Duc , Jaeger Walter , Tsuyuki Ross T , Barnes Joanne , Vohra Sunita
Published: March 2016

Purpose. Natural health products (NHPs), including melatonin, are widely used products. Despite the widespread assumption that all NHPs are safe, they contain pharmacologically active substances and can therefore have adverse effects and/or interact with pharmaceuticals. Objective: To investigate the mechanism underlying NHP interactions identified through the Pharmacy SONAR active surveillance study. Methods: Active surveillance was undertaken in community pharmacies to identify adverse events in patients who had recently taken NHPs together with conventional pharmaceuticals. For suspected NHP-pharmaceutical interactions, the possible mechanism of action was explored by in vitro analysis of samples of different products to identify cytochrome P450 enzyme (CYP) inhibition potential. Results: Active surveillance identified a 19-year-old male taking citalopram, nortriptyline and oxycodone concomitantly and who experienced severe sedation when melatonin was added to this regimen. In vitro analysis involving several melatonin products showed product-dependent inhibition of CYP1A2, CYP2C19 and CYP3A7. Conclusion: The adverse event was likely due to a primary pharmacokinetic interaction between melatonin and citalopram; although mechanistically, interactions affecting cytochrome P450-mediated metabolism may have occurred with all of these health products. A pharmacodynamic interaction may also be possible, but beyond the capacity of this study to establish.Key words: Melatonin, citalopram, nortriptyline, oxycodone, drug interaction. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Preparation and physicochemical characterization of Eudragit® RL100 Nanosuspension with potential for Ocular Delivery of Sulfacetamide
Authors: Mandal Bivash , Alexander Kenneth S , Riga Alan T
Published: March 2016

Purpose: Polymeric nanosuspension was prepared from an inert polymer resin (Eudragit® RL100) with the aim of improving the availability of sulfacetamide at the intraocular level to combat bacterial infections. Methods: Nanosuspensions were prepared by the solvent displacement method using acetone and Pluronic® F108 solution. Drug to polymer ratio was selected as formulation variable. Characterization of the nanosupension was performed by measuring particle size, zeta potential, Fourier Transform infrared spectra (FTIR), Differential Scanning Calorimetry (DSC), Powder X-Ray Diffraction (PXRD), drug entrapment efficiency and in vitro release. In addition, freeze drying, redispersibility and short term stability study at room temperature and at 40C were performed. Results: Spherical, uniform particles (size below 500 nm) with positive zeta potential were obtained. No significant chemical interactions between drug and polymer were observed in the solid state characterization of the freeze dried nanosuspension (FDN). Drug entrapment efficiency of the selected batch was increased by changing the pH of the external phase and addition of polymethyl methacrylate in the formulation. The prepared nanosuspension exhibited good stability after storage at room temperature and at 40C. Sucrose and Mannitol were used as cryoprotectants and exhibited good water redispersibility of the FDN. Conclusion: The results indicate that the formulation of sulfacetamide in Eudragit® RL100 nanosuspension could be utilized as potential delivery system for treating ocular bacterial infections.
Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond
Authors: Rao Praveen , Knaus Edward E.
Published: March 2016

Purpose. NSAIDs constitute an important class of drugs with therapeutic applications that have spanned several centuries. Treatment of inflammatory conditions such as rheumatoid arthritis (RA) and osteoarthritis (OA) starting from the classic drug aspirin to the recent rise and fall of selective COX-2 inhibitors has provided an enthralling evolution. Efforts to discover an ultimate magic bullet to treat inflammation continues to be an important drug design challenge. This review traces the origins of NSAIDs, their mechanism of action at the molecular level such as cyclooxygenase (COX) inhibition, development of selective COX-2 inhibitors, their adverse cardiovascular effects, and some recent developments targeted to the design of effective anti-inflammatory agents with reduced side effects. Methods. Literature data is presented describing important discoveries pertaining to the sequential development of classical NSAIDs and then selective COX-2 inhibitors, their mechanism of action, the structural basis for COX inhibition, and recent discoveries. Results. A brief history of the development of NSAIDs and the market withdrawal of selective COX-2 inhibitors is explained, followed by the description of prostaglandin biosynthesis, COX isoforms, structure and function. The structural basis for COX-1 and COX-2 inhibition is described along with methods used to evaluate COX-1/COX-2 inhibition. This is followed by a section that encompasses the major chemical classes of selective COX-2 inhibitors. The final section describes briefly some of the recent advances toward developing effective anti-inflammatory agents such as nitric oxide donor NO-NSAIDs, dual COX/LOX inhibitors and anti-TNF therapy. Conclusions. A great deal of progress has been made toward developing novel anti-inflammatory agents. In spite of the tremendous advances in the last decade, the design and development of a safe, effective and economical therapy for treating inflammatory conditions still presents a major challenge.