Category Archives: AMM 2017

The Influence of CYP2D6 Phenotype on the Pharmacokinetic Profile of Atomoxetine in Caucasian Healthy Subjects

Ioana Todor1, Dana Muntean1, Maria Neag2, Corina Bocsan2, Anca Buzoianu2, Laurian Vlase1, Daniel Leucuta3, Ana-Maria Gheldiu1, Adina Popa4, Corina Briciu4

1 University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Pharmacy, Department of Pharmaceutical Technology and Biopharmaceutics, Cluj-Napoca, Romania
2 University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Medicine, Department of Pharmacology, Toxicology and Clinical Pharmacology, Cluj- Napoca, Romania
3 University of Medicine and Pharmacy “Iuliu Hatieganu”, Department of Medical Informatics and Biostatistics, Cluj-Napoca, Romania
4 University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Pharmacy, Department of Clinical Pharmacy, Cluj-Napoca, Romania

DOI: 10.1515/amma-2017-0023

Objective: To analyze a potential phenotypic variation within the studied group based on the pharmacokinetic profile of atomoxetine and its active metabolite, and to further investigate the impact of CYP2D6 phenotype on atomoxetine pharmacokinetics.
Methods: The study was conducted as an open-label, non-randomized clinical trial which included 43 Caucasian healthy volunteers. Each subject received a single oral dose of atomoxetine 25 mg. Subsequently, atomoxetine and 4-hydroxyatomoxetine-O-glucuronide (glucuronidated active metabolite) plasma concentrations were determined and a noncompartmental method was used to calculate the pharmacokinetic parameters of both compounds. Further on, the CYP2D6 metabolic phenotype was assessed using the area under the curve (AUC) metabolic ratio (atomoxetine/ 4-hydroxyatomoxetine-O-glucuronide) and specific statistical tests (Lilliefors (Kolgomorov-Smirnov) and Anderson-Darling test). The phenotypic differences in atomoxetine disposition were identified based on the pharmacokinetic profile of the parent drug and its metabolite.
Results: The statistical analysis revealed that the AUC metabolic ratio data set did not follow a normal distribution. As a result, two different phenotypes were identified, respectively the poor metabolizer (PM) group which included 3 individuals and the extensive metabolizer (EM) group which comprised the remaining 40 subjects. Also, it was demonstrated that the metabolic phenotype significantly influenced atomoxetine pharmacokinetics, as PMs presented a 4.5-fold higher exposure to the parent drug and a 3.2-fold lower exposure to its metabolite in comparison to EMs.
Conclusions: The pharmacokinetic and statistical analysis emphasized the existence of 2 metabolic phenotypes: EMs and PMs. Furthermore, it was proved that the interphenotype variability had a marked influence on atomoxetine pharmacokinetic profile.

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Analytical Methodologies for the Stereoselective Determination of Sibutramine: An Overview

Alexandru Robert Vlad1, Gabriel Hancu1, Hajnal Kelemen1, Diana Ciurcă2, Amelia Tero-Vescan3

1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy, Tîrgu Mureş, Romania
2 Department of Organic Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy, Tîrgu Mureş, Romania
3 Department of Biochemistry, Faculty of Pharmacy, University of Medicine and Pharmacy, Tîrgu Mureş, Romania

DOI: 10.1515/amma-2017-0021

Sibutramine is a chiral anti-obesity drug which decreases food intake and increases energy expenditure. In therapy it is used as a racemic mixture; however both pharmacokinetic and pharmacodynamic data have revealed enantioselective behavior of sibutramine and its major active metabolites. Several chromatographic and electrophoretic analytical methods have been published so far for the chiral determination of sibutramine from pharmaceutical preparations and biological samples. The current paper aims to provide a systematic review of the stereochemical aspects and analytical methods used for the enantiodetermination of sibutramine and its active enantiomers covering the last 15 years.

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Silver Cation Coordination Study to AsW9 Ligand – A Trilacunar Arsenotungstate Compound

Lavinia Berta, Andrei Gâz, Francisc Boda, Augustin Curticapean

University of Medicine and Pharmacy of Tirgu Mures, Romania

DOI: 10.1515/amma-2017-0018

Objective: The main objective of this research is to find the coordination ratio between AsW9 and Ag+, as a preliminary study for synthesizing a new silver-arsenotungstate complex.
Material and method: The ligand:cation molar ratio in complexes was determined by conductometric and potentiometric titrations of AsW9 with silver salts: CH3COOAg, AgNO3.
Results: The ratio was obtained from the inflexion points of the curves when molar ratio was plotted versus conductivity, or from the equivalence point when silver added volume was plotted versus pH value. Each graphic shows one point of inflexion corres ponding to 1:1.54 ratio of AsW9:Ag+. In the same manner, the equivalent volumes determined by graphical method gave the ratio 1:1.53. The spectral results confirmed that a AsW9:Ag+ complex was formed since the ligand absorption maxima values have been changed from 190 nm to 197 nm in the case of using AgNO3 and 196 nm for CH3COOAg corresponding to the W=Od bond, and from 246,5 nm to 274 nm (AgNO3) and 270 nm (CH3COO-Ag+) for the W-Ob,c-W bond.
Conclusions: Silver cation exhibit a preference for AsW9 in a ratio of 3 to 2. This ratio can be associated to a sandwich type arrangement, with two trilacunary Keggin building blocks incorporating 3 metal cations in a tetrahedral geometry.

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Flow Cytometry Assessment of Bacterial and Yeast Induced Oxidative Burst in Peripheral Blood Phagocytes

Floredana-Laura Șular1,2, Minodora Dobreanu1,2

1 Discipline of Laboratory Medicine, University of Medicine and Pharmacy of Tîrgu Mureș, Romania
2 Central Laboratory, Emergency Clinical County Hospital of Tîrgu Mureș, Romania

DOI: 10.1515/amma-2017-0020

Objective: The aim of this study was to verify in our laboratory conditions the performance criteria of a commercial kit (PhagoburstTM, Glycotope Biotechnology) as described by the producers. We have also partially altered the use of the available kit by introducing a non-opsonized Candida albicans stimulus, in addition to the opsonized Escherichia coli stimulus provided by the manufacturer.
Material and methods: The peripheral blood samples of 6 clinically healthy adults were tested in triplicate according to the manufacturer recommendations. The intra-assay imprecision, as well as the ranges of neutrophil and monocyte burst activation triggered by various stimuli, were assessed.
Results: The activation range of granulocytes and monocytes was similar to the one described by the producer in the presence of E. coli (granulocytes: 78.45-99.43% versus 99.6-99.95%, average %CV of 1.53% versus 0.1%, monocytes: 54.63-92.33% versus 81.80-96.67, average %CV 6.92% versus 1.1%). The leukocyte range of activation in the presence of non-opsonized C. albicans was comparable to the one triggered by the fMLP (N-formyl-methionyl-leucyl-phenylalanine) stimulus.
Conclusion: The intra-assay precision obtained in our laboratory conditions, as well as the ranges of activated leukocytes, are comparable to the ones described by the producer when using E. coli as a stimulus. The present study shows that introducing an extra fungal stimulus for burst oxidation assessment could provide additional information regarding the non-specific cellular immune response, particularly in patients at risk for candidemia.

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Changes in Knee Joint Space Width in Treatment with a New Hyaluronic-Based Hydrogel

Octav Marius Russu, Andrei Marian Feier, Tudor Sorin Pop, Marcela Todoran, István Gergely

University of Medicine and Pharmacy Tirgu-Mures, Romania

DOI: 10.1515/amma-2017-0017

Objective: Our purpose was to assess the effect of a new hyaluronic acid-based (Hymovis®) injections on joint space width narrowing in patients diagnosed with knee osteoarthritis.
Methods: A prospective clinical trial was conducted in the Department of Orthopedics and Traumatology II from the Clinical County Hospital, Tîrgu Mureș, Romania. Thirty-five patients diagnosed with idiopathic knee osteoarthritis received two intraarticular injections with hyaluronic acid-based hydrogel (24 mg of hyaluronic acid/3 ml) at one-week interval. Anteroposterior radiographs were obtained before the injections, at six and twelve months after. Minimum joint space width was measured by two senior orthopaedics surgeons at each follow up. Each radiograph was measured again by the same evaluators two weeks apart.
Results: Thirty-one patients were present at the final follow-up. A minor reduction in mean weight was noticed (from 82.2 kg ± 16.2 kg to 80.9 kg ± 16.0, p > 0.398) without any correlation with joint space width narrowing. There were no major changes at the first follow up (6 months) regarding joint space narrowing. A reduction in joint space width was observed however at 12 months varying from 4.4 mm (SD ± 1.64, range 1.8-7.1) at the first assessment to 4.3 mm (SD ± 1.26, range 0.0-6.8) at the final follow-up but with no statistical difference (p=0.237).
Conclusion: No significant modification in joint space width at the final follow-up secondarily proved that two injections of Hymovis® may slow down narrowing in the knee joint space over a one-year period.

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Reduced Analgesics Consumption and Pain Intensity after Injections with a New Hyaluronic Acid in Patients with Knee Osteoarthritis

Octav Marius Russu, Andrei Marian Feier, Tudor Sorin Pop, Marcela Todoran, István Gergely

University of Medicine and Pharmacy Tîrgu Mures

DOI: 10.1515/amma-2017-0016

Objective: To determine the influence of a new intraarticular hyaluronic acid based hydrogel (Hymovis®) injections on the amount of analgesics consumption in patients diagnosed with primary knee OA.
Methods: A prospective, single-center study that included 35 patients, aged 45-80 years was conducted in our orthopaedics department. Patients received two intraarticular injections of hyaluronic acid (24 mg/3 ml; 500–730 kDa; Hymovis®) at one week apart. Follow-up was scheduled at 2 and 6 months after the injections. Assessment tools included Visual Analogue Scale (VAS) and an in-house designed questionnaire regarding analgesic consumption (quantity, period and product) during the follow-up.
Results: Compared to baseline, a significant amelioration in visual analogue scale was observed at six months’ follow-up (74.2mm ± 11.7 vs. 57.3mm ± 12.1; p < .0001). 28% (n=10) of the patients reduced their total analgesic consumption at two months after the injections. At final follow-up, the analgesic intake was reduced by more than 50% in almost every case.
Conclusions: Intraarticular administered injections with a novel hyaluronan-based hydrogel (Hymovis®) may reduce the amount of analgesic consumption and self-reported pain intensity in patients with knee OA.

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Evaluation of Early Postoperative Cognitive Dysfunction Incidence and Involved Neurocognitive Functions in Patients with Cardiac and Noncardiac Surgery Under General Anesthesia

Carmen Sircuţa1, Tunde Lucza2, Mihaly Veres1, Ildiko Szomoru3, Leonard Azamfirei1

1 University of Medicine and Pharmacy Tirgu Mures, Romania
2 Emergency Institute for Cardiovascular Diseases and Transplantation Tirgu Mures, Romania
3 Emergency Clinical County Hospital of Tirgu Mures, Romania

DOI: 10.1515/amma-2017-0012

Objective: To analyse postoperative cognitive dysfunction’s (POCD) incidence and cognitive areas involved, in patients with cardiac and general surgery.
Material and Methods: Prospective observational study on 130 patients undergoing general or heart surgery on cardiopulmonary bypass, under general anesthesia. Two groups, 65 members each. Group A had a heart surgery and group B a noncardiac surgery. The same type of anesthetic drugs were used. All patients completed the Montreal Cognitive Assesment (MoCA) questionnaire: preoperative, 24 hours after stopping any medicine acting on central nervous system and 7 days postoperative. We compared the MoCA scores obtained on different cognitive domains in this moments for each group of patients, for neurocognitive functions: visuo-spatial executive, naming, attention, verbal fluency, abstraction, recall, orientation, final score. We compared the scores between the two groups at 24 hours and 7 days postoperatively for the same domains.
Results: POCD was found at 24 hours testing in both groups. At 7 days postoperatively POCD was not found in any of the groups. There was no statistically significant difference in total final score between two groups at 24 hours nor at 7 days postoperative testing. There are significant differences between the two groups, with lower score in cardiac group in 5 of 7 fields at 24 hours testing, with the persistence of difference in 2 of 7 fields at 7 days.
Conclusions: Overall POCD was present at 24 hours but was not found at 7 days testing for none of the groups. POCD is present in some neurocognitive domains and this depends on surgery type.

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The Risk of Using Poppy Seed Tea Made from Several Varieties Available on the Romanian Market

Mircea Dumitru Croitoru, Ibolya Fülöp, Maria-Raluca Irimia-Constantin, Erzsébet Varga, Hajnal Kelemen, Erzsébet Fogarasi, Luana-Maria Faliboga

University of Medicine and Pharmacy of Tîrgu Mureș, Tîrgu Mureş, Romania

DOI: 10.1515/amma-2017-0013

Objective: the number of alkaloids like morphine and codeine found in poppy seeds used in food industry are monitored by a directive given by European Food Safety Authority. Based on this regulation the aim of the study was to determine the quantity of morphine and codeine from several brands of poppy seeds.
Methods: an HPLC-UV method (205 nm) was developed to measure the quantity of morphine and codeine. Sample preparation was made using recipes posted on Drugs Forum by some users. Limits of detection were not determined because the lowest concentration from the reference (0.1 µg/ml) detected morphine concentrations that are far lower than a limit of toxicological concern.
Results: The concentrations, which were found, ranged between Below the Level of Toxicological Concern (BLTC) – 243.26 mg/kg for morphine and BLTC – 88.58 mg/kg for codeine using several methods of preparation.
Conclusions: one can observe that there are some brands of poppy seeds which do not respect the regulation about the amount of morphine and codeine. The high amount of morphine in some samples suggests that there are different varieties of poppy seeds, which can be used for an illicit purpose and can lead to addiction or even overdose in some cases.

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Clinical Outcomes after Regenerative Periodontal Therapy with Emdogain

Gabriela Felicia Beresescu1, Alina Ormenisan2, Melinda Szekely3, Monica Monea4, Adriana Monea4

1 University of Medicine and Pharmacy Tirgu Mures, Romania
2 Department of Oral and Maxillofacial Surgery, Faculty of Dental Medicine, University of Medicine and Pharmacy Tirgu Mures, Romania
3 Department of Tooth and Dental Arch Morphology, Faculty of Dental Medicine, University of Medicine and Pharmacy Tirgu Mures, Romania
4 Department of Odontology and Oral Pathology, Faculty of Dental Medicine, University of Medicine and Pharmacy Tirgu Mures, Romania

DOI: 10.1515/amma-2017-0015

Objective: Regeneration is defined as a reconstruction of a lost part of the body in such a way that the structure and function of the lost tissue are completely restored. The aim of this study is to compare the clinical outcomes of intrabony defects treatment using regenerative periodontal therapy with enamel matrix proteins (Emdogain, EMD) with a control group.
Methods: Ten patients with chronic periodontitis were included in this randomized, controlled clinical study. Two groups received conservative periodontal therapy. In the test group, different teeth received regenerative treatment with EMD. In the control group teeth received solely conservative periodontal therapy. Pocket depth probing (PD) and bone reduction (based on X rays) were registered at baseline and after eight months in both groups. In the control group
Results: Both groups showed a significant reduction of PD. The teeth treated with EMD showed a significant attachment gain. Within the test group, the radiographic examination of the teeth treated with EMD showed no significant change, whereas the teeth in the control group showed significant bone reduction.
Conclusions: Intrabony defects in teeth treaded with EMD exhibit a substantially higher gain in clinical attachment and defect filling. The use of EMD in dental practice can prevent further bone loss.

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Preparation and Characterization of Levofloxacin-Loaded Nanofibers as Potential Wound Dressings

Noémi Pásztor, Emőke Rédai, Zoltán-István Szabó, Emese Sipos

University of Medicine and Pharmacy of Tîrgu Mureș, Romania

DOI: 10.1515/amma-2017-0014

Objective: The study aimed at obtaining and characterizing levofloxacin-loaded, poly(ε-caprolactone) electrospun nanofiber formulations to be used as antibacterial wound dressings.
Methods: Drug-loaded nanofibers were obtained by the electrospinning process and their morphology was determined using scanning electron microscopy. Structural analysis of the prepared nanofibers was carried out using differential scanning calorimetry and dissolution testing was performed in order to determine drug release.
Results: Both nanofiberous formulations (containing 20 % and 50 % w/w levofloxacin) showed dimensions in the range of few hundred nanometers. Thermograms indicated that the formulation containing 20% levofloxacin was totally amorphized, showing a rapid release of the active, in 20 minutes.
Conclusions: The poly(ε-caprolactone)-based electrospun nanofibers, containing levofloxacin presented suitable characteristics for obtaining potential antibacterial wound dressings.

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