Category Archives: AMM 2019

Silent Ischemic Stroke Was Revealed after Screening for Cognitive Dysfunction in a Hypertensive Patient with New Onset Atrial Fibrillation – Case Report

Tünde Pál1, Zoltan Preg2, Enikő Nemes-Nagy2, Robert Gabriel Tripon2, Beáta Baróti2,
Márta Germán-Salló2

1. Emergency County Hospital Targu Mures, Romania
2. University of Medicine and Pharmacy Science and Technology of Targu Mures, Romania

DOI: 10.2478/amma-2019-0018

Introduction: Hypertension is one of the most important modifiable risk factor related to cognitive decline and dementia. However, screening for cognitive dysfunction is not part of the routine clinical assessment.
Case presentation: In this report, we present the case of a 75 year old hypertensive male patient with new-onset atrial fibrillation, admitted to the Cardiovascular Rehabilitation Clinic Târgu Mureș. Apart from the routine clinical assessment, the evaluation of cognitive functions was performed with three different screening instruments which identified cognitive dysfunction. Depressive state was assessed with the shortened 13 items form of the Beck Depression Inventory BDI-13 (BDI-13) and it showed moderate depression which could influence the results of cognitive tests. Detection of cognitive impairment was followed by magnetic resonance imaging, which revealed not only hypertension specific microvascular impairment but also a sequelae of a former stroke in the territory of the left middle cerebral artery and a possible meningioma.
Conclusion: Screening for cognitive dysfunction in high-risk hypertensive patients can be easily performed and in several cases like ours, can unmask silent cerebrovascular pathologies, leading to prognostic and therapeutic consequences.

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Atomoxetine and Duloxetine: Evaluation of a Potential Pharmacokinetic Drug-Drug Interaction

Ioana Todor1, Adina Popa2, Dana Muntean1, Maria Neag3, Ana-Maria Gheldiu4, Corina Briciu2, Daniel Leucuta5, Laurian Vlase1

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 Pharmacy, Department of Clinical Pharmacy, Cluj-Napoca, Romania
3. University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Medicine, Department of Pharmacology, Toxicology and Clinical Pharmacology, Cluj-Napoca, Romania
4. University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Pharmacy, Department of Pharmaceutical Botany, Cluj-Napoca, Romania
5. University of Medicine and Pharmacy ”Iuliu Hatieganu”, Faculty of Medicine, Department of Medical Informatics and Biostatistics, Cluj-Napoca, Romania

DOI: 10.2478/amma-2019-0017

Objective: The present research aimed to investigate whether a pharmacokinetic drug interaction exists between atomoxetine, a substrate of CYP2D6 and duloxetine, an enzymatic inhibitor of the same metabolic pathway.
Methods: Twenty-three healthy volunteers were enrolled in an open-label, non-randomized, sequential, 2-period clinical study. During the trial, they received a single dose of atomoxetine 25 mg (Period 1:Reference) followed by a combination of atomoxetine 25 mg and duloxetine 30 mg, after a pretreatment regimen with duloxetine 30-60 mg/day for 4 days (Period 2:Test). The pharmacokinetic parameters of atomoxetine and its main metabolite (4-hydroxyatomoxetine-O-glucuronide) were estimated using a non-compartmental approach and statistical tests were used to compare these parameters between study periods.
Results: A total of 22 subjects, extensive metabolizers (EMs), were considered for the final report of the study findings. Duloxetine influenced the plasma concentration-time profile of both parent drug and its glucuronidated metabolite. The pharmacokinetic and statistical analysis revealed that pretreatment with the enzymatic inhibitor increased the mean atomoxetine AUC0–t (from 1151.19±686.52 to 1495.54±812.40 [ng*h/mL]) and AUC0–∞ (from 1229.15±751.04 to 1619.37±955.01 [ng*h/mL]) while kel was decreased and the mean t1/2 was prolonged. With regard to 4-hydroxyatomoxetine-O-glucuronide, Cmax was reduced from 688.76±270.27 to 621.60±248.82 [ng/mL] after coadministration of atomoxetine and duloxetine.
Conclusions: Duloxetine had an impact on the pharmacokinetics of atomoxetine as it increased the exposure to the latter by ~30%. Although the magnitude of this pharmacokinetic interaction is rather small, a potential clinical relevance cannot be ruled out with certainty without further investigation.

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MicroRNAs as Biomarkers and Therapeutic Targets in Heart Failure

István Adorján Szabó1, Atilla Frigy2

1. Department of Physiopathology, University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Romania
2. Department of Internal Medicine IV, University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Romania

DOI: 10.2478/amma-2019-0016

Heart failure still represents a real challenge both in everyday practice and research, due to the complex issues related to its pathogenesis and management. Humoral biomarkers have emerged in the last decades as useful tools in the diagnosis, risk stratification and guiding the treatment of heart failure. These molecules are related to different pathological and adaptive processes, like myocardial injury, neurohormonal activation and cardiac remodeling, their most widespread representatives being the natriuretic peptides (e.g. NT-proBNP). The role of altered gene expression and transcription as the basis of myocardial structural and functional changes in heart failure is largely recognized. MicroRNAs (miRNAs) are non-coding RNAs which have a major role in post-transcriptional gene expression by interfering with messenger RNA molecules. Our short review summarizes the molecular biology of miRNAs and their possible role as biomarkers in the diagnosis and prognosis of heart failure. Furthermore, the therapeutical perspectives conferred by these molecules are also presented.
Keywords: miRNA, biomarkers, heart failure

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The Statistical Analysis of Pharmacokinetic Parameters in the Context of Bioequivalence Testing of Two Anthelmintic Formulas Based on Ivermectine and Triclabendazole in Sheep

Lenard Farczadi1, Laurian Vlase2, Orsolya Melles3, Ramona Tolomeiu4, Octavia Tamas-Krumpe4, Andreea Buta4, Laurentiu Ognean4

1. University of Medicine, Pharmacy, Science and Technology of Targu Mures, Romania
2. “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
3. Clinical and Analytical Research Center Vim Spectrum
4. University of Agricultural Science and Veterinary Medicine Cluj-Napoca, Romania

DOI: 10.2478/amma-2019-0015

Conducting bioequivalence studies is an essential step during the market authorization process of generic pharmaceutical formulations, for both human or veterinary use. The aim of the present study was to evaluate the pharmacokinetics of triclabendazole sulphoxide, the main metabolite of triclabendazole, and ivermectin in order to evaluate the bioavailability and bioequivalence of a novel sheep anthelmintic formulation of oral suspension for sheep treatment containing triclabendazole 50 mg/mL and ivermectin 1 mg/mL compared to the reference product. In order to determine relative bioavailability of the test product with respect to the reference product the study was conducted on 36 clinically healthy sheep, following an unicentric, randomized, cross-over, two-sequence, two-treatment and 14-day wash-out study design. For the determination of triclabendazole sulphoxide and ivermectin sheep plasma concentrations, two rapid, selective high performance liquid chromatography coupled with mass spectrometry (LC-MS/MS) methods were developed and validated. The measured plasma concentrations of triclabendazole sulphoxide and ivermectin were used for the pharmacokinetic analysis and the determination of bioequivalence between the test product with regards to the reference product. The noncompartmental analysis of the pharmacokinetic data for both triclabendazole sulphoxide and ivermectin showed similarities between first-order kinetics of the test and reference product. The relevant pharmacokinetic parameters (Cmax, AUClast, AUCtot) were determined and the bioequivalence between the test and reference product could be concluded.

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Postoperative Lymphorrhagia – a Possible Complication Following Cephalic Duodenopancreatectomy

Adrian Tudor1,2, Marian Botoncea1, Cedric Kwizera1, Bianca Cornelia Tudor3,4, Cosmin Nicolescu1,2, Călin Molnar1,5

1. First Surgical Department, Emergency Clinical County Hospital of Târgu Mures, Mures, Romania
2. Anatomy and Embryology Department, University of Medicine, Pharmacy, Sciences and Technology of Targu Mures, Romania
3. Lab Medicine, Clinical County Hospital of Târgu Mureș, Romania
4. Microbiology, virology and parasitology Department, University of Medicine, Pharmacy, Sciences and Techology of Târgu Mureș, Romania
5. Surgery I Department, University of Medicine, Pharmacy, Sciences and Technology of Târgu Mures, Romania

DOI: 10.2478/amma-2019-0013

Surgery associated with lymphadenectomy may sometimes result in a lymphorrhagia, which usually resolves spontaneously within a few days, sometimes becoming a refractory complication to the treatment. In the case of large flows, particular attention should be paid to hydroelectrolytic and protein losses. We present the case of a patient with persistent lymphorrhagia after a cephalic duodenopancreatectomy for a pancreatic head tumor. From the 5th postoperative day, the patient had a milky-like secretion on the subhepatic drainage tube. The discharge rate was variable, between 500 and 1500 ml per day, requiring parenteral administration of amino acids, plasma and electrolyte solutions. The postoperative progression was slowly favorable, with the patient discharge on the 25th day following surgery. There are several treatment options for a lymphorrhagia following an extended lymphadenectomy, from intensive parenteral therapy to peritoneal-venous shunt or ligation of the lymphatic vessel responsible for the production of lymphorrhagia. In this case the conservative treatment had a favorable result.

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The Complication Rates of Oral Anticoagulation Therapy in Deep Venous Thrombosis

Ionela Silivastru (Cozlea)1, Arthur-Atilla Keresztesi2, Gabriela Asofie (Keresztesi)1, Daniel Cozlea1,3, Daniela Ecaterina Dobru1,3

1. Targu Mures County Emergency Clinical Hospital, Romania
2. County Department of Forensic Medicine Ialomita, INML “Mina Minovici” Bucuresti, Romania
3. University of Medicine, Pharmacy, Sciences and Technology of Targu Mures, Romania

DOI: 10.2478/amma-2019-0012

The objective of the current study is to evaluate the complication rates (embolic and hemorrhagic events) in deep venous thrombosis (DVT) patients on different types of oral anticoagulation therapy (OAC): direct oral anticoagulant therapy and vitamin K antagonist therapy.
Methods: A number of 62 DVT patients were included and divided in two groups, depending on the type of oral anticoagulation therapy administered. The first group was composed of patients treated with direct oral anticoagulant treatment (Dabigatran, Rivaroxaban) and the second group was composed of patients treated with vitamin K antagonist (Acenocumarol). General data, including BMI and comorbidities were noted. Embolic and hemorrhagic events were noticed.
Results: in the first group of patients (DOAC therapy), a number of 34 patients were included (14 of them with BMI higher than 25 kg/m2 and 14 with concomitant atrial fibrillation), while the second group comprised of 28 patients treated with VKA (21 of them with a high BMI and only 3 of them with atrial fibrillation). After a mean period of 36 months of anticoagulant therapy, complications were present in 17 patients, hematuria (8 episodes) and pulmonary embolism (4 cases) were the most frequent, with no difference regarding the treatment applied. Conclusion: No statistically significant difference was encountered regarding embolic and hemorrhagic event rates in our deep vein thrombosis patients.

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Development and Validation of an UV-Spectrophotometric Method for the Assay of Strontium Ranelate and HPLC Stability Testing from Bulk and Pharmaceutical Dosage Form

Béla Kovács1, Réka Molnár2, Előd Ernő Nagy3, Éva Katalin Kelemen4, Blanka Székely-Szentmiklósi3, István Székely-Szentmiklósi4,5, Boglárka Kovács-Deák6, Árpád Gyéresi7

1. University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, Romania
2. First Department of Internal Medicine, Faculty of Medicine, University of Szeged, Hungary
3. Department of Biochemistry and Environmental Chemistry, Faculty of Pharmacy, University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, Romania
4. Gedeon Richter, Târgu Mureș, Romania
5. Department of Pharmaceutical Industry and Management, Faculty of Pharmacy, University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, Romania
6. Salvator Pharmacy, Târgu Mureș, Romania
7. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, Romania

DOI: 10.2478/amma-2019-0014

Objective: The present work offers a fast, reliable and easy UV spectrophotometric method for the assay of strontium ranelate from bulk samples and pharmaceutical dosage form.
Methods: The proposed method uses 0.1% V/V trichloroacetic acid as dissolution medium for spectrophotometric analysis, by signal detection at 321 nm. The method was validated according to the currently in-force international guidelines for linearity, accuracy, precision, robustness, limit of detection and quantification.
Results: The method was found to be linear in the range of 5-100 µg mL-1 (R2 > 0.999). Method accuracy was found in-between 98.87-100.41%, showing good linear correlation as well (R2 = 0.9997). The concentrations for limit of detection and limit of quantitation were found 1.13 µg mL-1 and 3.77 µg mL-1, resp. The proposed method showed good intra- and interday precision, with low RSD values of 0.53-1.24% and 1.11%, resp.
Conclusions: Stability studies performed by both HPLC and UV spectrophotometric methods revealed that the active substance is highly susceptible to acidic hydrolysis, oxidation and exposure to high temperature.

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Analytical Quality by Design with the Lifecycle Approach: A Modern Epitome for Analytical Method Development

Maher Abdulrazzaq Alhakeem1, Mihaela Violeta Ghica2, Cristina Dinu Pîrvu2, Valentina Anuța2, Lăcrămioara Popa2

1. University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
2. Department of Physical and Colloidal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania

DOI: 10.2478/amma-2019-0010

Quality by Design is the methodical method to development concept that starts with the predefined objects. The method put emphasis on the process of development of a product, the control process, which is built on risk management and comprehensive knowledge of science. The concept of QbD applied to analytical method development is known now as AQbD (Analytical Quality by Design). Comprehension of the Analytical Target Profile (ATP) and the risk assessment for the variables that can have an impact on the productivity of the developed analytical method can be the main principles of the AQbD. Inside the method operable design region (MODR), the AQbD permits the movements of the analytical methods. This paper has been produced to discuss various views of analytical scientists, the comparison with conventional methods, and the phases of the analytical techniques.

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Development and Validation of an UHPLC Method for Ostarine Determination in Dietary Supplements

Amalia Miklos1, Amelia Tero-Vescan1, Lénárd Farczádi2,3, Daniela-Lucia Muntean1

1. Faculty of Pharmacy, University of Medicine, Pharmacy, Sciences and Technology of Tîrgu Mureș, Tîrgu Mureş, Romania
2. Center for Advanced Medical and Pharmaceutical Research (CCAMF), University of Medicine, Pharmacy, Sciences and Technology of Tîrgu Mureș, Tîrgu Mureş, Romania
3. Faculty of Pharmacy, University of Medicine and Pharmacy „Iuliu Hațieganu” Cluj-Napoca, Cluj-Napoca, Romania

DOI: 10.2478/amma-2019-0008

Objective: The purpose of this study was to develop a low-cost, yet sensitive and precise UHPLC method for the quantitative determination of ostarine from dietary supplements (DS) for athletes. The analytical performance of the method was verified on a DS legally acquired from a specialized website for athletes. The uniformity of mass and content of the ostarine DS was also verified.
Methods: For the quantitative determination of ostarine a UHPLC method was developed and validated. The separation was performed using a reversed-phase C18 column, using a mixture of 75% methanol: 25% formic acid 0.1% in isocratic elution, at a flow rate of 0.5 ml/min. The uniformity of mass and content of DS was performed following the methodology described in the European Pharmacopoeia 7th Edition.
Results: The validated method was specific and linear on the concentration range of 1-25 µg/ml and was precise and accurate at all concentration levels, according to the official guidelines for validating analytical methods. An average mass of 510 mg content was obtained for the ostarine capsules, with an RSD of 2.41%. Regarding the uniformity of the content, an average of 4.65 mg ostarine/capsule was obtained with an RSD of 1.05%.
Conclusions: The developed UHPLC method was suitable, rapid, sensitive and allowed quantitative determination of active substance content in a DS with ostarine (92.91% ostarine/capsule from 5 mg ostarine/capsule declared by the manufacturer).

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Urinary Sodium/Potassium Ratio in Acute Kidney Injury Accurately Differentiates Prerenal Azotemia from Acute Tubular Necrosis

Theodore Shankel, Stewart Shankel

Redlands Community Hospital, Redlands, USA

DOI: 10.2478/amma-2019-0011

Objective: To develop a more accurate, cost effective, non-invasive test to differentiate between pre-renal renal failure (PRA) and acute tubular necrosis (ATN) in acute kidney injury (AKI).
Methods: Urine sodium/potassium (Na/K) ratios were compared with fractional excretion of sodium (FeNa) and renal failure index (RFI) as well as other commonly used indices to differentiate patients with PRA from ATN. Patients with a rise in serum creatinine > 0.5 mg/d identified from medical records for a six- to eighteen-month period, were reviewed and categorized either as PRA or ATN based on presenting findings, course in hospital or renal biopsy. All patients had urinary sodium and potassium, creatinine, and serum creatinine done.
Results: The Na/K was < 1 in PRA and > 1 in ATN, correctly identifying all 42 cases of PRA and all 28 patients with ATN. The FeNa was >1 and misdiagnosed 9 of 42 patients with PRA and was >1 and correctly diagnosed all patients with ATN. The RFI was >1 and misdiagnosed 11 of 42 patients with PRA but was >1 and correctly diagnosed all patients with ATN. The BUN/creatinine ratio, urine sodium concentration and U/P creatinine ratio all had a very poor correlation with the correct diagnosis.
Conclusion: The Na/K ratio correctly diagnosed all 42 cases of PRA and all 28 cases of ATN. It is easy to do, is cost effective, non-invasive, and is useful for following patients with PRA to see if and when they develop ATN.

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