Calculation of drug dose which produces 'all-or-nothing' response in 50% of subjects (effective dose 50) using probits

There is a number of drugs which produce responses that are clinically visible according to the principle 'all-or-nothing', i.e. the effect on certain dose either happens, or not. In order to calculate the dose of such drug that would cause response in 50% of exposed patients (effective dose 50 or abbreviated ED50), probit analysis is necessary. The essence of this application of probit analysis is formation of linear regression between logarithm of the drug doses and probits, i.e. numbers of standard deviations that responses to corresponding doses deviate from the most frequent response (assuming normal distribution of responses to certain doses of the drug). ED50 is further calculated from equation of this linear regression as the dose corresponding to probit value five

Analysing factors which influence treatment outcomes by multivariable linear regression

Multivariable linear regression is a procedure of building mathematical model of straight line with several independent variables which are added one to another and to a constant to give value of dependent variable, i.e. of outcome. Dependent variable has to be continuous and numeric, while independent variables may be of both numeric and categorical type. Multivariable linear regression is very useful method for testing influence of multiple independent variables on a treatment outcome (dependent variable). With this method it is possible not only to estimate whether certain independent variable may influence the outcome significantly, but also to quantify this influence and compare strength of influence between the variables. Multivariable linear regression is especially useful method for analyzing data of observational clinical studies, particularly 'cross-sectional' ones

Efficacy and safety of local lysozyme treatment in patients with oral mucositis after chemotherapy and radiotherapy

This observational clinical study was composed of two substudies: a non-comparative one (n = 166), testing only lysozyme-based compounds (LBCs), and a comparative substudy (n = 275), testing both LBCs and bicarbonate-based local compounds (BBCs) on the healing of oral mucositis during radio- or chemotherapy. The density of ulcerations has decreased significantly after the treatment with lysozyme in both substudies. The density of ulcerations in the radiotherapy group was lower in patients treated with LBCs compared to patients treated with BBCs (p < 0.001). In the chemotherapy group, reduction of ulceration density was similar with both LBCs and BBCs. The LBCs reduced pain intensity during the intake of solid food and speech more than BBCs in both patient cohorts (p < 0.05). In the radiotherapy cohort, pain intensity when consuming liquid foods was reduced more with LBCs than with BBCs (p < 0.05). No adverse events were recorded. This study demonstrates the advantages of treating oral mucositis during radiotherapy or chemotherapy with LBCs

Non-oncological drug-induced blood disorders: a cost of illness study using the microcosting Methodology - study plan [protocol]

Drug-induced disorder „can result from unanticipated or anticipated drug effects“ (1). The prevalence of hematological adverse drug reactions (ADR) in chemotherapeutics is expected to be high; for non-chemotherapeutics, there is insufficient epidemiological data, although a spontaneous reporting system is mandatory in a drug's life cycle (2-6). ADR is considered to be the fifth cause of death, with the hospitalization rate caused by ADR estimated to be between 0.9-7.9% (7-8), while one study suggests that about „10 to 20% of hospitalized patients will experience ADRs during their stay“ (9). Frequency data on hospital admissions due to hematological ADR vary between studies, e.g., 9% (7) up to 26.5% (10). The study by Abu et al. categorized major ADR types based on system disorders, where hematologic ADR encountered 9.9-15.2% of ADRs (9). The same study estimated costs per ADR from 65.00 to 12,129.90 USD, whereas costs were generally lower when the micro- costing approach was used (9). A cost-of-illness (COI) study should be performed to precisely determine the costs generated by ADR. COI studies measure the economic burden of an illness on society, health insurance funds, or patients. Jefferson et al. (2000) defined “the aim of COI studies is descriptive: to itemize, value, and sum the costs of a particular problem with the aim of giving an idea of its economic burden“ (11). There are different methods of conducting this type of study, such as prevalence‐based, incidence‐based, or econometric approaches, with again different approaches (e.g., prospective, retrospective; top-down, bottom-up…) or with different perspectives of COI studies (such as societal, health care system, third-party payer) (11). However, micro-costing studies represent the gold standard for conducting COI studies (12). Only a few cost drivers of HADR have been proven to date, e.g., prolonged in-hospital stay, costs of using drugs, and transfusion costs (13-14).STUDY PLA

Factors associated with hematological adverse reactions of drugs authorized via the centralized procedure

Serious hematological adverse drug reactions (HADRs) may lead to or prolong hospitalization and even cause death. The aim of this study was to determine the regulatory factors associated with HADRs caused by drugs that were authorized up to July 2023 by the European Medicines Agency (EMA) and to evaluate the frequency of HADRs. Using a cross-sectional approach, the type and frequency of HADRs were collected from the Summaries of Product Characteristics of Drugs Authorized by the EMA and analyzed within proprietary, nonproprietary, and biosimilar/biological frameworks. Multivariate statistical analysis was used to investigate the associations of generic status, biosimilar status, conditional approval, exceptional circumstances, accelerated assessment, orphan drug status, years on the market, administration route, and inclusion on the Essential Medicines List (EML) with HADRs. In total, 54.78% of proprietary drugs were associated with HADRs at any frequency, while anemia, leucopenia, and thrombocytopenia were observed in approximately 36% of the patients. The predictors of any HADR, anemia, and thrombocytopenia of any frequency are generic status, biosimilar status, and inclusion on the EML, while the only protective factor is the administration route. Biosimilars and their originator biologicals have similar frequencies of HADRs; the only exception is somatropin. Knowledge of the regulatory factors associated with HADRs could help clinicians address monitoring issues when new drugs are introduced for the treatment of patients

The role of a pharmacist in prevention and detection of OTC drug interactions: Nominal group technique

Introduction: Nowadays number of newly approved OTC medicines continuously increases, which can make certain difficulties in drug dispensing process. This fact particularly relates to drug-drug interactions-problems due to lack of data and insufficient of knowledge about the interactions. Aim: To identify the problems pharmacists face when dispensing OTC drugs and to recommend concrete ideas and methods for improving system for detecting OTC drugs interactions. Participants and method: The study was carried out in accordance with methodological principles of nominal group technique. Two meetings of nominal group were conducted, enrolling pharmacists employed in public pharmacies. During the meetings, moderator imposed aset of questions to participants, who gave answers in the form of individual statements. In order to examine agreement of the participants about the individual statements, at the end of both sessions the statements were rated on a Likert's scale. Meetings were recorded and audio recordings later used for qualitative analysis. Results: Nine pharmacists of both sex (7/2 females/males) participated in this study. Average age of the participants was 25.0±1.0 years. During nominal group meetings, participants presented 30 statements on 7 research questions, and after the second meeting agreement was reached about 29 of them. Qualitative analysis of data indicated three categories of statements: (1) pharmacists' knowledge of OTC drugs interactions, (2) problems pharmacists face when dispensing OTC drugs and (3) options of improving system for prevention and detection of OTC drugs interactions. Conclusion: For adequate prevention of potential OTC drugs interactions it is necessary to make guidelines with recommendations referring to proper dispensing procedure and to use regularly available online interaction checkers

Risk factors for severe dental anxiety among medical students

Background/Aim. Severe dental anxiety (SDA) is the most severe form of dental anxiety, thus the aim of this study was to determine the factors associated with SDA in students of health-related disciplines. Methods. In this case-control study the cases were students with severe dental anxiety. The study was conducted at the Faculty of Medical Sciences, University of Kragujevac, Serbia. The participants were undergraduate students attending lectures during spring semester 2010/2011 (n = 1,812). A random sample of 800 students was assessed for the association between various risk factors and the severe dental anxiety. The main outcome measures were the data on demographics, dental anxiety, habits concerning oral hygiene, nutrition, general anxiety and (co)morbidity which were collected from the study participants by semi-structured questionnaire. Results. Less frequent visits to the dentist (OR adjusted = 7.02 [2.65; 18.60]) and visiting the dentist only when there is a dental problem (OR adjusted = 8.08 [1.28; 50.93]) were associated with severe dental anxiety. The same was true for improper oral hygiene (OR adjusted = 4.25 [1.16; 15.60]). Factors as changing toothbrush more frequently (OR adjusted = 0.33 [0.14; 0.76]) and having chronic disease (OR adjusted = 0.01 [0.00; 0.09]) were inversely associated with severe dental anxiety. The level of education of students was not associated with severe dental anxiety. Conclusion. Inappropriate oral hygiene, less frequent changes of a toothbrush and less frequent visits to the dentist are important risk factors for severe dental anxiety. [Projekat Ministarstva nauke Republike Srbije, br. 175007

POPULATION PHARMACOKINETICS OF 2-OXO-CLOPIDOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROME

The aim of the study was to develop a population pharmacokinetic (PK) model for clearance of 2-oxo-clopidogrel in patients with acute coronary syndrome (ACS). Population pharmacokinetic analysis was performed by using 72 plasma concentrations from the same number of patients (mean age of 60.82±10.76 years; total body weight (TBW) of 73.63±9.67 kg) with ACS using non-linear mixed-effect modeling (NONMEM). Validation of the final PPK model was carried out through the bootstrap analysis with 200 runs and it was used to estimate the predictive performance of the pharmacokinetic model. The typical mean value for 2-oxo-clopidogrel clearance (CL), estimated by the base model (without covariates), in our population was 39.2 l h−1.The value of aspartate transaminase and co-medication with digoxin were determinants of a derived population model. The final regression model for the clearance of 2-oxo-clopidogrel was the following: CL (lh-1) = 1.7 + 1.31*AST + 115*DIGOXIN. The derived PK model describes the clearance of 2-oxo-clopidogrel in patients with ACS, showing that the value of aspartate transaminase and co-medication with digoxin are the most important covariate. This finding will provide the basis for future PK studies

Pharmacological analysis of muscarinic receptor subtypes in smooth muscle from the body of the stomach

Маdа su M1, M2 i M3 pоdtipоvi muskаrinskоg rеcеptоrа bili idеntifikоvаni u glаtkim mišićimа žеlucа žаbе, pаcоvа, psа i svinjе, pоdtipоvi оvоg rеcеptоrа nisu bili ispitаni u žеlucu čоvеkа i mаčkе. Cilј оvе tеzе је biо dа sе idеntifikuјu i оkаrаktеrišu pоdtipоvi muskаrinskоg rеcеptоrа u lоngitudinаlnоm i cirkulаrnоm mišićnоm slојu tеlа žеlucа čоvеkа i mаčkе. Fаrmаkоlоškа аnаlizа pоdtipоvа muskаrinskоg rеcеptоrа је sprоvеdеnа nа izоlоvаnim prеpаrаtimа cirkulаrnоg i lоngitudinаlnоg mišićnоg slоја tеlа žеlucа čоvеkа (42 uzоrkа) i mаčkе (109 uzоrаkа). Аctilhоlinоm-indukоvаnе tоničkе kоntrаkciје cirkulаrnоg mišićnоg slоја tеlа žеlucа čоvеkа su snаžnо blоkirаli hеksоcikliјum (pA2=9.92), tеlеnzеpin (pA2=9.86), skоpоlаmin butilbrоmid (pA2=9.68), trihеksifеnidil (pA2=9.42) i аtrоpin (pA2=8.91), umеrеnо pirеnzеpin (pA2=7.41) i slаbо gаlаmin (pA2=5.60) i pFHHSiD (pA2=5.84). Тоničkе kоntrаkciје lоngitudinаlnоg mišićnоg slоја tеlа žеlucа čоvеkа su snаžnо blоkirаli hеksоcikliјum (pA2=9.19), tеlеnzеpin (pA2=9.37), skоpоlаmin butilbrоmid (pA2=8.67), trihеksifеnidil (pA2=9.72) i аtrоpin (pA2=8.56), umеrеnо gаlаmin (pA2=7.18) i slаbо pirеnzеpin (pA2=6.25) i pFHHSiD (pA2 niје izrаčunаtо). Тоničkе kоntrаkciје cirkulаrnоg mišićnоg slоја tеlа žеlucа mаčkе su blоkirаli snаžnо trihеksifеnidil (pA2=9.20), аtrоpin (pA2=8.96), hеksоcikliјum (pA2=8.94), skоpоlаmin butilbrоmid (pA2=8.38) i pFHHSiD (pA2=7.98), а umеrеnо gаlаmin (pA2=7.32), pаnkurоniјum (pA2=7.28), pirеnzеpin (pA2=7.14) i tеlеnzеpin (pA2=7.09). Тоničkе kоntrаkciје lоngitudinаlnоg mišićnоg slоја tеlа žеlucа mаčkе su blоkirаli snаžnо аtrоpin (pA2=9.57), hеksоcikliјum (pA2=9.43), trihеksifеnidil (pA2=9.13), tеlеnzеpin (pA2=8.65) i pFHHSiD (pA2=8.88), umеrеnо gаlаmin (pA2=7.97) i pаnkurоniјum (pA2=8.06), а slаbо pirеnzеpin (pA2=6.87) i skоpоlаmin butilbrоmid (pA2=6.41). U cirkulаrnоm i lоngitudinаlnоm mišićnоm slојu žеlucа čоvеkа dоminirа М1 pоdtip muskаrinskоg rеcеptоrа, dоk su u cirkulаrnоm i lоngitudinаlnоm mišićnоm slојu žеlucа mаčkе dоminаntni М1 i М3 pоdtipоvi.Although M1, M2 and M3 muscarinic receptor subtypes were identified in smooth muscles of the stomach from frog, rat, dog and swine, subtypes of this receptor were not characterized in human and feline stomach. The aim of this thesis was to identify and characterize muscarinic receptor subtypes in longitudinal and circular smooth muscle layers from the body of human and feline stomach. Pharmacological analysis of muscarinic receptor subtypes was conducted on isolated preparations of circular and longitudinal smooth muscle layer from the body of human (42 specimens) and feline (109 specimens) stomach. Acetylcholine-induced tonic contractions of circular muscle layer from the body of human stomach were blocked strongly by hexocyclium (pA2=9.92), telenzepine (pA2=9.86), scopolamine butylbromide (pA2=9.68), trihexyphenidyl (pA2=9.42) and atropine (pA2=8.91), moderately by pirenzepine (pA2=7.41) and weakly by gallamine (pA2=5.60) and pFHHSiD (pA2=5.84). Tonic contractions of longitudinal muscle layer from the body of human stomach were blocked strongly by hexocyclium (pA2=9.19), telenzepine (pA2=9.37), scopolamine butylbromide (pA2=8.67), trihexyphenidyl (pA2=9.72) and atropine (pA2=8.56), moderately by gallamine (pA2=7.18) and weakly by pirenzepine (pA2=6.25) and pFHHSiD (pA2 not calculated). Tonic contractions of circular muscle layer from the body of feline stomach were blocked strongly by trihexyphenidyl (pA2=9.20), atropine (pA2=8.96), hexocyclium (pA2=8.94), scopolamine butylbromide (pA2=8.38) and pFHHSiD (pA2=7.98) and moderately by gallamine (pA2=7.32), pancuronium (pA2=7.28), pirenzepine (pA2=7.14) and telenzepine (pA2=7.09). Tonic contractions of longitudinal muscle layer from the body of feline stomach were blocked strongly by atropine (pA2=9.57), hexocyclium (pA2=9.43), trihexyphenidyl (pA2=9.13), telenzepine (pA2=8.65) and pFHHSiD (pA2=8.88), moderately by gallamine (pA2=7.97) and pancuronium (pA2=8.06), and weakly by pirenzepine (pA2=6.87) and scopolamine butylbromide (pA2=6.41). Circular and longitudinal muscle layers from the human stomach are dominated by M1 muscarinic receptor subtype, while in the circular and longitudinal muscle layers from the feline stomach dominant subtypes of muscarinic receptor are both M1 and M3

Neutropenia induced by non-cytotoxic drugs

Polymorphonuclear neutrophils make about 60-70% of all leucocytes in adults. Neutropenia is defined by neutrophil count below 1.5 h 109/l. It could be classified as mild, moderate and severe, based on the following absolute neutrophil count: 1-1.5 h 109/l, 0.5-1 h 109/l, and < 0.5 h 109/l. Incidence of drug-induced neutropenia is 3-10 cases per million. Drug-induced neutropenia emerges suddenly, and develops a few hours to 1-2 days after administration of the offending drug. There are several mechanisms of neutropenia induced by non-cytotoxic drugs: (1) drug binding to neutrophil membrane, formation of hapten and induction of immune response which destroys neutrophil; (2) induction of neutrophil apoptosis; (3) formation of immune complexes; (4) induction of autoantibodies and complement activation with destruction of neutrophils; (5) dose-dependent inhibition of granulopoesis; and (6) direct toxic effect on myeloid precursors. Treatment of patients with drug-induced neutropenia consists of the offending drug discontinuation, maintenance of strict hygiene and administration of granulocyte-colony stimulating factors in the case of severe neutropenia