Search results for: common drug combinations

Authors: Mustafa Malki, Ewan R. Pearson

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Tools utilized by health care practitioners to flag potential adverse drug reactions secondary to drug-drug interactions ignore individual genetic variation, which has the potential to markedly alter the severity of these interactions. To our best knowledge, there have been limited published studies on the impact of genetic variation on drug-drug interactions. Therefore, our aim in this project is the discovery of previously unrecognized, clinically important drug-drug-gene interactions (DDGIs) within the list of most commonly used drug combinations in the UK. The UKBB database was utilized to identify the top most frequently prescribed drug combinations in the UK with at least one route of interaction (over than 200 combinations were identified). We have recognised 37 common and unique interacting genes considering all of our drug combinations. Out of around 600 potential genetic variants found in these 37 genes, 100 variants have met the selection criteria (common variant with minor allele frequency ≥ 5%, independence, and has passed HWE test). The association between these variants and the use of each of our top drug combinations has been tested with a case-control analysis under the log-additive model. As the data is cross-sectional, drug intolerance has been identified from the genotype distribution as presented by the lower percentage of patients carrying the risky allele and on the drug combination compared to those free of these risk factors and vice versa with drug tolerance. In GoDARTs database, the same list of common drug combinations identified by the UKBB was utilized here with the same list of candidate genetic variants but with the addition of 14 new SNPs so that we have a total of 114 variants which have met the selection criteria in GoDARTs. From the list of the top 200 drug combinations, we have selected 28 combinations where the two drugs in each combination are known to be used chronically. For each of our 28 combinations, three drug response phenotypes have been identified (drug stop/switch, dose decrease, or dose increase of any of the two drugs during their interaction). The association between each of the three phenotypes belonging to each of our 28 drug combinations has been tested against our 114 candidate genetic variants. The results show replication of four findings between both databases : (1) Omeprazole +Amitriptyline +rs2246709 (A > G) variant in CYP3A4 gene (p-values and ORs with the UKBB and GoDARTs respectively = 0.048,0.037,0.92,and 0.52 (dose increase phenotype)) (2) Simvastatin + Ranitidine + rs9332197 (T > C) variant in CYP2C9 gene (0.024,0.032,0.81, and 5.75 (drug stop/switch phenotype)) (3) Atorvastatin + Doxazosin + rs9282564 (T > C) variant in ABCB1 gene (0.0015,0.0095,1.58,and 3.14 (drug stop/switch phenotype)) (4) Simvastatin + Nifedipine + rs2257401 (C > G) variant in CYP3A7 gene (0.025,0.019,0.77,and 0.30 (drug stop/switch phenotype)). In addition, some other non-replicated, but interesting, significant findings were detected. Our work also provides a great source of information for researchers interested in DD, DG, or DDG interactions studies as it has highlighted the top common drug combinations in the UK with recognizing 114 significant genetic variants related to drugs' pharmacokinetic.

Keywords: adverse drug reactions, common drug combinations, drug-drug-gene interactions, pharmacogenomics

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Authors: Sara Ataei, Molouk Hadjibabaie, Shirinsadat Badri, Amirhossein Moslehi, Iman Karimzadeh, Ardeshir Ghavamzadeh

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Purpose: To assess the pattern and probable risk factors for moderate and major drug–drug interactions in a referral hematology-oncology ward in Iran. Methods: All patients admitted to hematology–oncology ward of Dr. Shariati Hospital during a 6-month period and received at least two anti-cancer or non-anti-cancer medications simultaneously were included. All being scheduled anti-cancer and non-anti-cancer medications both prescribed and administered during ward stay were considered for drug–drug interaction screening by Lexi-Interact On- Desktop software. Results: One hundred and eighty-five drug–drug interactions with moderate or major severity were detected from 83 patients. Most of drug–drug interactions (69.73 %) were classified as pharmacokinetics. Fluconazole (25.95 %) was the most commonly offending medication in drug–drug interactions. Interaction of sulfamethoxazole-trimethoprim with fluconazole was the most common drug–drug interaction (27.27 %). Vincristine with imatinib was the only identified interaction between two anti-cancer agents. The number of administered medications during ward stay was considered as an independent risk factor for developing a drug–drug interaction. Conclusions: Potential moderate or major drug–drug interactions occur frequently in patients with hematological malignancies or related diseases. Performing larger standard studies are required to assess the real clinical and economical effects of drug–drug interactions on patients with hematological and non-hematological malignancies.

Keywords: drug–drug interactions, hematology–oncology ward, hematological malignancies

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Authors: Abhijit Trailokya, Kamlesh Patel

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Background: Hypertension is a common disease seen in clinical practice and is associated with high morbidity and mortality. Many patients require combination therapy for the management of hypertension. Objective: To evaluate co-morbidities, risk factors and management practices of hypertension in Indian population. Material and methods: A total of 1596 hypertensive adult patients received anti-hypertensive medications were studied in a cross-sectional, multi-centric, non-interventional, observational registry. Statistical analysis: Categories or nominal data was expressed as numbers with percentages. Continuous variables were analyzed by descriptive statistics using mean, SD, and range Chi square test was used for in between group comparison. Results: The study included 73.50% males and 26.50% females. Overweight (50.50%) and obesity (30.01%) was common in the hypertensive patients (n=903). A total of 54.76% patients had history of smoking. Alcohol use (33.08%), sedentary life style (32.96%) and history of tobacco chewing (17.92%) were the other lifestyle habits of hypertensive patients. Diabetes (36.03%) and dyslipidemia (39.79%) history was common in these patients. Family history of hypertension and diabetes was seen in 82.21% and 45.99% patients respectively. Most (89.16%) patients were treated with combination of antihypertensive agents. ARBs were the by far most commonly used agents (91.98%) followed by calcium channel blockers (68.23%) and diuretics (60.21%). ARB was the most (80.35%) preferred agent as monotherapy. ARB was also the most common agent as a component of dual therapy, four drug and five drug combinations. Conclusion: Most of the hypertensive patients need combination treatment with antihypertensive agents. ARBs are the most preferred agents as monotherapy for the management of hypertension. ARBs are also very commonly used as a component of combination therapy during hypertension management.

Keywords: antihypertensive, hypertension, management, ARB

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Authors: Jagdish S. Patel, Piyush Chudasama

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Context: Over-expression of P-glycoprotein (P-gp) plays critical role in absorption of many drug candidates which results into lower bioavailability of the drug. P-glycoprotein also over expresses in many pathological conditions like diabetes, affecting the drug therapy. Modulation of P-gp expression using inhibitors can help in designing novel formulation enhancing the bioavailability of the drug in question. Objectives: The main focus of the study was to develop advanced glycation end products (AGEs) induced P-gp over expression in Caco-2 cells. Curcumin, piperine and epigallocatechin gallate were used to evaluate their P-gp inhibitory action using combinatorial approach. Materials and methods: Methylglyoxal (MG) induced P-gp over expression was checked in Caco-2 cells using real time PCR. P-gp inhibitory effects of the phytochemicals were measured after induction with MG alone and in combination of any two compounds. Cytotoxicity of each of the phytochemical was evaluated using MTT assay. Results: Induction with MG (100mM) significantly induced the over expression of P-glycoprotein in Caco-2 cells after 24 hr. Curcumin, piperine and epigallocatechin gallate alone significantly reduced the level of P-gp within 6 hr of treatment period monitored by real time PCR. The combination of any two phytochemical also down regulated the expression of P-gp in cells. Combinations of Curcumin and epigallocatechin gallate have shown significant down regulation when compared with other two combinations. Conclusions: Combinatorial approach for down regulating the expression of P-gp, in pathological conditions like diabetes, has demonstrated promising approach for therapeutic purpose.

Keywords: p-glycoprotein, curcumin, piperine, epigallocatechin gallate, p-gp inhibition

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Authors: Sarah E. Casey

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Epilepsy is the most common neurological disorder in children and approximately one-third of children with epilepsy have seizures that are uncontrolled on anticonvulsants alone. Cannabidiol is shown to be an effective treatment at reducing the amount of breakthrough seizures experienced by children with drug resistant epilepsy. Improvements in quality of life and overall condition were noted during cannabidiol treatment. Adverse side effects were experienced and were generally mild to moderate in nature. Additional double-blind, controlled studies with a more diverse sample population and standardized dosing are needed to ensure the efficacy and safety of cannabidiol use in children with drug resistant epilepsy.

Keywords: cannabis, drug resistant epilepsy, children, epilepsy

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Authors: A. Hilsana, Vinay U. Rao, M. Sudhakar

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Even though a number of non-steroidal anti-inflammatory drugs (NSAIDS) are available with different chemistries, they share a common solubility characteristic that is they are relatively more soluble in alkaline environment and practically insoluble in acidic environment. This work deals with developing a wax matrix drug delivery platform for controlled delivery of three model NSAIDS, Diclofenac sodium (DNa), Mefenamic acid (MA) and Naproxen (NPX) using the melt granulation technique. The aim of developing the platform was to have a general understanding on how an erodible matrix system modulates drug delivery rate and extent and how it can be optimized to give a delivery system which shall release the drug as per a common target product profile (TPP). Commonly used waxes like Cetostearyl alcohol and stearic acid were used singly an in combination to achieve a TPP of not 15 to 35% in 1 hour and not less than 80% Q in 24 hours. Full factorial design of experiments was followed for optimization of the formulation.

Keywords: NSAIDs, controlled delivery, target product profile, melt granulation

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Authors: Blessing A. Aderibigbe

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Combination therapy is a treatment approach that is used to prevent the emergence of drug resistance. This approach is used for the treatment of many chronic and infectious diseases. Potentiating agents are currently explored in combination therapy, resulting in excellent therapeutic outcomes. Breast cancer and malaria are two chronic conditions responsible globally for high death rates. In this research, a class of polymer-drug conjugates containing potentiating agents with either antimalarial or anticancer drugs were prepared by Michael Addition Polymerization reaction and ring-opening polymerization reaction. Conjugation of potentiating agents with bioactive compounds into the polymers resulted in conjugates with good water solubility, highly selective and non-toxic. In vitro cytotoxicity and in vitro antiplasmodial evaluation on the conjugates revealed that the conjugates were more effective when compared to the free drugs. The drug release studies further showed that the release profile of the drugs from the conjugates was sustained. The findings revealed the potential of polymer-drug conjugates to overcome drug toxicity and drug resistance, which is common with the currently used antimalarial and anticancer drugs.

Keywords: anticancer, antimalarials, combination therapy, polymer-drug conjugates

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Authors: Khaliun Nyambayar, Nomindari Azzaya, Batkhuyag Purevjav

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Pharmacovigilance was officially introduced in Mongolia in 2003, in accordance with the Health Minister Order 183 for the registry of adverse drug reactions (ADR), approved in 2006 and was reviewed in 2010. This study was designed to evaluate the incidence and common types of adverse drug reactions among hospitalized children, the frequency of adverse drug reaction reported by health care providers, and the follow-up processes resulting from adverse drug reactions. A retrospective study of paediatric patients who experienced an adverse drug reaction from 2015 to 2019, extracted from the “yellow” card at the State Research Center for Maternal and Child Health, (city). A total of 417 adverse drug reactions were reported with an overall incidence was 80 (21.5%). Adverse reactions resulting from the use of antibiotics (particularly gentamycin, cephalosporins, and vancomycin) were usually mild. ADR’s were reported by physicians and nurses (93.8%), pharmacists (6.25%). Although documentation of physician notification occurred for 93% of adverse drug reactions, only 29% of cases were documented in the patient's medical chart, 13% included follow-up education for individuals involved, and 10% were updated in the allergy profile of the hospital computer system. Measures to improve the detection and reporting of adverse drug reactions by all health care professionals should be improved, to enhance our understanding of the nature and impact of these reactions in children.

Keywords: adverse drug reaction, pediatric, yellow card, Mongolia

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Authors: Bhumika Wadhwa, Fayaz Malik

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The serine/threonine protein kinase B (PKB) also known as Akt, is one of the multifaceted kinase in human kinome, existing in three isoforms. Akt plays a vital role in phosphoinositide 3-kinase (PI3K) mediated oncogenesis in various malignancies and is one of the attractive targets for cancer drug discovery. The functional significance of an individual isoform of Akt is not redundant in cancer cell proliferation and metastasis instead Akt isoforms play distinct roles during metastasis; thereby regulating EMT. This study aims to determine isoform specific functions of Akt in cancer. The results obtained suggest that Akt1 restrict tumor invasion, whereas Akt2 promotes cell migration and invasion by various techniques like MTT, wound healing and invasion assay. Similarly, qRT-PCR also revealed that Akt3 has shown promising results in promoting cancer cell migration. Contrary to pro-oncogenic properties attributed to Akt, it is to be understood how various isoforms of Akt compensates each other in the regulation of common pathways during cancer progression and drug resistance. In conclusion, this study aims to target selective isoforms which is essential to inhibit cancer. However, the question now is whether, and how much, Akt inhibition will be tolerated in the clinic remains to be answered and the experiments will have to address the question of which combinations of newly devised Akt isoform specific inhibitors exert a favourable therapeutic effect in in vivo models of cancer to provide the therapeutic window with minimal toxicity.

Keywords: Akt isoforms, cancer, drug resistance, epithelial mesenchymal transition

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Authors: Baljinder Singh, Navneet Sharma

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The skin can be used as the site for drug administration for continuous transdermal drug infusion into the systemic circulation. For the continuous diffusion/penetration of the drugs through the intact skin surface membrane-moderated systems, matrix dispersion type systems, adhesive diffusion controlled systems and micro reservoir systems have been developed. Various penetration enhancers are used for the drug diffusion through skin. In matrix dispersion type systems, the drug is dispersed in the solvent along with the polymers and solvent allowed to evaporate forming a homogeneous drug-polymer matrix. Matrix type systems were developed in the present study. In the present work, an attempt has been made to develop a matrix-type transdermal therapeutic system comprising of ondansetron-HCl with different ratios of hydrophilic and hydrophobic polymeric combinations using solvent evaporation technique. The physicochemical compatibility of the drug and the polymers was studied by infrared spectroscopy. The results obtained showed no physical-chemical incompatibility between the drug and the polymers. The patches were further subjected to various physical evaluations along with the in-vitro permeation studies using rat skin. On the basis of results obtained form the in vitro study and physical evaluation, the patches containing hydrophilic polymers i.e. polyvinyl alcohol and poly vinyl pyrrolidone with oleic acid as the penetration enhancer(5%) were considered as suitable for large scale manufacturing with a backing layer and a suitable adhesive membrane.

Keywords: transdermal drug delivery, penetration enhancers, hydrophilic and hydrophobic polymers, ondansetron HCl

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Authors: Gayathri Vijayakumar, Preethi Baskaran

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The effluents that are let down by the industries mix with the water bodies and drastically affect the aquatic life, which leads to pollution and bio magnifications. Effluents mostly contain chemicals, heavy metals etc., and cause toxicity to the environment. The pharmaceutical industries too contribute. The by-products and other unwanted waste are discharged without any treatment; these causes DNA damage and affect behavior of aquatic life. The study was conducted on koi carp (Cyprinus carpio) the ornamental variety of common carp. A two week long study was conducted on them using common anti-depressant drug (Diazepam) in various concentrations. These drugs are known to cause behavioral damage and organ malfunctions (muscle twitch). The histopathological study conducted showed permanent muscle twitching and lesions in the fish samples studied. The sociability was also affected in the span of 14 days. Higher concentrations of this drug showed severe damage in the muscle structures. Thus, this drug can cause adverse effects on marine ecosystem and eventually cause bio magnification of drug by running through the food chain.

Keywords: pollution, toxicity, bio-magnifications, koi carp, muscle twitch, diazepam, histopathology

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Authors: Desalegn Feyissa Desu

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Drug therapy problem is a significant challenge to provide high quality health care service for the patients. It is associated with morbidity, mortality, increased hospital stay, and reduced quality of life. Moreover, pediatric patients are quite susceptible to drug therapy problems. Thus this study aimed to assess drug therapy problem and its contributing factors among pediatric patients diagnosed with infectious disease admitted to pediatric ward of Jimma university medical center, from April 1 to June 30, 2018. Prospective observational study was conducted among pediatric patients with infectious disease admitted from April 01 to June 30, 2018. Drug therapy problems were identified by using Cipolle’s and strand’s drug related problem classification method. Patient’s written informed consent was obtained after explaining the purpose of the study. Patient’s specific data were collected using structured questionnaire. Data were entered into Epi data version 4.0.2 and then exported to statistical software package version 21.0 for analysis. To identify predictors of drug therapy problems occurrence, multiple stepwise backward logistic regression analysis was done. The 95% CI was used to show the accuracy of data analysis and statistical significance was considered at p-value < 0.05. A total of 304 pediatric patients were included in the study. Of these, 226(74.3%) patients had at least one drug therapy problem during their hospital stay. A total of 356 drug therapy problems were identified among two hundred twenty six patients. Non-compliance (28.65%) and dose too low (27.53%) were the most common type of drug related problems while disease comorbidity [AOR=3.39, 95% CI= (1.89-6.08)], Polypharmacy [AOR=3.16, 95% CI= (1.61-6.20)] and more than six days stay in hospital [AOR=3.37, 95% CI= (1.71-6.64) were independent predictors of drug therapy problem occurrence. Drug therapy problems were common in pediatric patients with infectious disease in the study area. Presence of comorbidity, polypharmacy and prolonged hospital stay were the predictors of drug therapy problem in study area. Therefore, to overcome the significant gaps in pediatric pharmaceutical care, clinical pharmacists, Pediatricians, and other health care professionals have to work in collaboration.

Keywords: drug therapy problem, pediatric, infectious disease, Ethiopia

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Authors: Ahlam Ali, Katrina Lappin, Jaine Blayney, Ken Mills

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Leukaemia is the most frequently (30%) occurring type of paediatric cancer. Of these, approximately 80% are acute lymphoblastic leukaemia (ALL) with acute myeloid leukaemia (AML) cases making up the remaining 20% alongside other leukaemias. Unfortunately, children with AML do not have promising prognosis with only 60% surviving 5 years or longer. It has been highlighted recently the need for age-specific therapies for AML patients, with paediatric AML cases having a different mutational landscape compared with AML diagnosed in adult patients. Drug Repurposing is a recognized strategy in drug discovery and development where an already approved drug is used for diseases other than originally indicated. We aim to identify novel combination therapies with the promise of providing alternative more effective and less toxic induction therapy options. Our in-silico analysis highlighted ‘cell death and survival’ as an aberrant, potentially targetable pathway in paediatric AML patients. On this basis, 83 apoptotic inducing compounds were screened. A preliminary single agent screen was also performed to eliminate potentially toxic chemicals, then drugs were constructed into a pooled library with 10 drugs per well over 160 wells, with 45 possible pairs and 120 triples in each well. Seven cell lines were used during this study to represent the clonality of AML in paediatric patients (Kasumi-1, CMK, CMS, MV11-14, PL21, THP1, MOLM-13). Cytotoxicity was assessed up to 72 hours using CellTox™ Green reagent. Fluorescence readings were normalized to a DMSO control. Z-Score was assigned to each well based on the mean and standard deviation of all the data. Combinations with a Z-Score <2 were eliminated and the remaining wells were taken forward for further analysis. A well was considered ‘successful’ if each drug individually demonstrated a Z-Score <2, while the combination exhibited a Z-Score >2. Each of the ten compounds in one well (155) had minimal or no effect as single agents on cell viability however, a combination of two or more of the compounds resulted in a substantial increase in cell death, therefore the ten compounds were de-convoluted to identify a possible synergistic pair/triple combinations. The screen identified two possible ‘novel’ drug pairing, with BCL2 inhibitor ABT-737, combined with either a CDK inhibitor Purvalanol A, or AKT/ PI3K inhibitor LY294002. (ABT-737- 100 nM+ Purvalanol A- 1 µM) (ABT-737- 100 nM+ LY294002- 2 µM). Three possible triple combinations were identified (LY2409881+Akti-1/2+Purvalanol A, SU9516+Akti-1/2+Purvalanol A, and ABT-737+LY2409881+Purvalanol A), which will be taken forward for examining their efficacy at varying concentrations and dosing schedules, across multiple paediatric AML cell lines for optimisation of maximum synergy. We believe that our combination screening approach has potential for future use with a larger cohort of drugs including FDA approved compounds and patient material.

Keywords: AML, drug repurposing, ABT-737, apoptosis

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Authors: Deepika Bhaskar, Neena Wadehra, Megha Gulati, Aruna Narula, R. Vishnu, Gunjan Katyal

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With drug resistance becoming widespread in Plasmodium falciparum infections, development of the alternative drugs is the desired strategy for prevention and cure of malaria. Three drug targets were selected to screen promising drug molecules from the GSK library of around 14000 molecules. Using an in silico structure-based drug designing approach, the differences in binding energies of the substrate and inhibitor were exploited between target sites of parasite and human to design a drug molecule against Plasmodium. The docking studies have shown several promising molecules from GSK library with more effective binding as compared to the already known inhibitors for the drug targets. Though stronger interaction has been shown by several molecules as compare to reference, few molecules have shown the potential as drug candidates though in vitro studies are required to validate the results.

Keywords: plasmodium, malaria, drug targets, in silico studies

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Authors: Kamel Abd Elaziz Mohamed

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Introduction: Drug related problems (DRPs) are of major concern, affecting patients of both sex. They impose considerable economic burden on the society and the health-care systems. Aim of the work: The aim of this work was to identify and categorize drug-related problems in adult intensive care unit. Patients and methods: The study was a prospective, observational study as eighty six patients were included. They were consecutively admitted to ICU through the emergency room or transferred from the general ward due to DRPs. Parameters included in the study as length of stay in ICU, need for cardiovascular support or mechanical ventilation, dialysis, as well as APACHE II score were recorded. Results: Drug related problems represent 3.6% of the total ICU admission. The median (range) of APACHE II score for 86 patients included in the study was 17 (10-23), and length of ICU stay was 2.4 (1.5-4.2) days. In 45 patients (52%), DRP was drug over dose (group 1), while other DRP was present in the other 41 patients (48%, group 11). Patients in group 1 were older (39 years versus 32 years in group 11), with significant impaired renal function. The need of inotropic drugs and mechanical ventilation as well as the length of stay (LOS) in ICU was significantly higher in group 1. There were no significant difference in GCS between both groups, however APACHE II score was significantly higher in group 1. Only four patients (4.6%) were admitted by suicidal attempt as well as three patients (3.4%) due to trauma drug-related admissions, all were in (group 1). Nineteen percent of the patients had drug related problem due to hypoglycaemic medication followed by tranquilizer (15%). Adverse drug effect followed by failure to receive medication were the most causes of drug problem in (group11).The total mortality rate was 4.6%, all of them were eventually non preventable. Conclusion: The critically ill patients admitted due to drug related problems represented a small proportion (3.6%) of admissions to the ICU. Hypoglycaemic medication was one of the most common causes of admission by drug related problems.

Keywords: drug related problems, ICU, cost, safety

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Authors: Ephrem Mebratu Dagnew, Mohammed Biset Ayalew, Gizework Alemnew Mekonnen, Alehegn Bishaw Geremew, Ousman Abubeker Abdela

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Objective: To assess the prevalence of drug-related problems and associated factors among adult psychiatric inpatients. Method: Hospital-based multicenter cross-sectional observational study was conducted from April to July 2021 at five randomly selected hospitals in North-west Ethiopia. A total of 325 consecutively sampled patients participated in the study. Clinical pharmacists assessed the DRPs based on clinical judgment supported by updated evidence-based diseases guidelines. A Medscape drug-interactions checker was used to check drug-drug interactions. The results were summarized using descriptive statistics, including frequency, mean, and standard deviation. Odds ratio (OR) with 95% confidence interval were also computed for each variable for the corresponding P-value. The value of P ≤ 0.05 was considered statistically significant. Result : From the total of 325 study participants, more than half of them (52.9%) were females and the mean age ± (standard deviation) was 30.8±11.3 years. At least one drug-related problem was recorded from 60.9%, 95% CI (55.7-65.8) of study participants with a mean of 0.6±0.49 per patient. Need additional drug therapy was the most common DRP (22.8%), followed by non-adherence to medicine (20.6%) and adverse drug reactions (11%), respectively. Factors independently associated with drug-related problems were rural residence [AOR=1.96,95%CI:1.01-2.84, P-value=0.046], self-employed [AOR=6.0 ,95% CI: 1.0-36.9, P-value=0.035] and alcohol drinkers [AOR=6.40,95%CI:1.12-37.5, p-value=0.034]. Conclusion: The prevalence of drug-related problems among adult psychiatric patients admitted to psychiatric wards was high. Healthcare providers give more attention to tackling these problems. Being a rural residence, self-employed, and Alcohol drinkers were associated with drug-related problems.

Keywords: psychiatric patients, drug-relatedproblems, multicenter, Ethiopia

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Authors: Judith Stein, Elfriede Friedmann

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The injection of a drug into the vitreous body for the treatment of retinal diseases like wet aged-related macular degeneration (AMD) is the most common medical intervention worldwide. We develop mathematical models for drug transport in the vitreous body of a human eye to analyse the impact of different rheological models of the vitreous on drug distribution. In addition to the convection diffusion equation characterizing the drug spreading, we use porous media modeling for the healthy vitreous with a dense collagen network and include the steady permeating flow of the aqueous humor described by Darcy's law driven by a pressure drop. Additionally, the vitreous body in a healthy human eye behaves like a viscoelastic gel through the collagen fibers suspended in the network of hyaluronic acid and acts as a drug depot for the treatment of retinal diseases. In a completely liquefied vitreous, we couple the drug diffusion with the classical Navier-Stokes flow equations. We prove the global existence and uniqueness of the weak solution of the developed initial-boundary value problem describing the drug distribution in the healthy vitreous considering the permeating aqueous humor flow in the realistic three-dimensional setting. In particular, for the drug diffusion equation, results from the literature are extended from homogeneous Dirichlet boundary conditions to our mixed boundary conditions that describe the eye with the Galerkin's method using Cauchy-Schwarz inequality and trace theorem. Because there is only a small effective drug concentration range and higher concentrations may be toxic, the ability to model the drug transport could improve the therapy by considering patient individual differences and give a better understanding of the physiological and pathological processes in the vitreous.

Keywords: coupled PDE systems, drug diffusion, mixed boundary conditions, vitreous body

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Authors: Pimporn Thongmuang

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The import value of antimicrobial drugs reached approximately fifteen million Baht in 2010, considered as the highest import value of all modern drugs, and this value is rising every year. Antimicrobials are considered the hazardous drugs by the Ministry of Public Health. This research was conducted in order to investigate the past knowledge of drug use and Antimicrobial drug use behavior. A total of 757 students were selected as the samples out of a population of 1,800 students. This selected students had the experience of Antimicrobial drugs use a year ago. A questionnaire was utilized in this research. The findings put on the view that knowledge gained by the students about proper use of antimicrobial drugs was not brought into practice. This suggests that the education procedure regarding drug use needs adjustment. And therefore the findings of this research are expected to be utilized as guidelines for educating people about the proper use of antimicrobial drugs. At a broader perspective, correct drug use behavior of the public may potentially reduce drug cost of the Ministry of Public Health of Thailand.

Keywords: drug use knowledge, antimicrobial drugs, drug use behavior, drug

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Authors: Debalke Dale, Bezabh Geneta, Yohannes Amene, Yordanos Bergene, Mohammed Yimam

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Background: A drug therapy problem (DTP) is an event or circumstance that involves drug therapies that actually or potentially interfere with the desired outcome and requires professional judgment to resolve. Heart failure is an emerging worldwide threat whose prevalence and health loss burden constantly increase, especially in the young and in low-to-middle-income countries. There is a lack of population-based incidence and prevalence of heart failure (HF) studies in sub-Saharan African countries, including Ethiopia. Objective: The aim of this study was designed to assess drug therapy problems and associated factors among patients with HF in the medical ward of Arba Minch General Hospital(AGH), Ethiopia, from June 5 to August 20, 2022. Methods: A retrospective cross-sectional study was conducted among 180 patients with HF who were admitted to the medical ward of AGH. Data were collected from patients' cards by using questionnaires. The data were categorized and analyzed by using SPSS version 25.0 software, and data were presented in tables and words based on the nature of the data. Result: Out of the total, 85 (57.6%) were females, and 113 (75.3%) patients were aged over fifty years. Of the 150 study participants, 86 (57.3%) patients had at least one DTP identified, and a total of 116 DTPs were identified, which is 0.77 DTPs per patient. The most common types of DTP were unnecessary drug therapy (32%), followed by the need for additional drug therapy (36%), and dose too low (15%). Patients who used polypharmacy were 5.86 (AOR) times more likely to develop DTPs than those who did not (95% CI = 1.625–16.536, P = 0.005), and patients with more co-morbid conditions developed 3.68 (AOR) times more DTPs than those who had fewer co-morbidities (95% CI = 1.28–10.5, P = 0.015). Conclusion: The results of this study indicated that drug therapy problems were common among medical ward patients with heart failure. These problems are adversely affecting the treatment outcomes of patients, so it requires the special attention of healthcare professionals to optimize them.

Keywords: heart failure, drug therapy problems, Arba Minch general hospital, Ethiopia

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Authors: Paresh Patel, Harshit Patel

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Superficial fungal skin infection is among the most common skin disease. The drug administration through skin has received attention due to several advantages: Avoidance of significant pre-systemic metabolism, drug levels within the therapeutic window, drugs with short biological half-lives, decreased side effects, the non-invasive character, and very high acceptance.

Keywords: transdermal spray, ketoconazole, Eudragit® RLPO, therapeutic window

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Authors: Rashini Maduka, C. R. Wijesinghe, A. R. Weerasinghe

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Drug-drug interactions (DDIs) can happen when two or more drugs are taken together. Today DDIs have become a serious health issue due to adverse drug effects. In vivo and in vitro methods for identifying DDIs are time-consuming and costly. Therefore, in-silico-based approaches are preferred in DDI identification. Most machine learning models for DDI prediction are used chemical and biological drug properties as features. However, some drug features are not available and costly to extract. Therefore, it is better to make automatic feature engineering. Furthermore, people who have diabetes already suffer from other diseases and take more than one medicine together. Then adverse drug effects may happen to diabetic patients and cause unpleasant reactions in the body. In this study, we present a model with a graph convolutional autoencoder and a graph decoder using a dataset from DrugBank version 5.1.3. The main objective of the model is to identify unknown interactions between antidiabetic drugs and the drugs taken by diabetic patients for other diseases. We considered automatic feature engineering and used Known DDIs only as the input for the model. Our model has achieved 0.86 in AUC and 0.86 in AP.

Keywords: drug-drug interaction prediction, graph embedding, graph convolutional networks, adverse drug effects

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Authors: Farzad Jalilian, Mehdi Mirzaei Alavijeh, Fazel Zinat Motlagh

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Social support is an important benchmark of health for people in avoidance conditions. The main goal of this study was to determine the three kinds of social support (family, friend and other significant) to drug cessation among male addicts, in Kermanshah, the west of Iran. This cross-sectional study was conducted among 132 addicts, randomly selected to participate voluntarily in the study. Data were collected from conduct interviews based on standard questionnaire and analyzed by using SPSS-18 at 95% significance level. The majority of addicts were young (Mean: 30.4 years), and with little education. Opium (36.4%), Crack (21.2%), and Methamphetamine (12.9%) were the predominant drugs. Inabilities to reject the offer and having addict friends are the most often reasons for drug usage. Almost, 18.9% reported history of drug injection. 43.2% of the participants already did drug cessation at least once. Logistic regression showed the family support (OR = 1.110), age (OR = 1.106) and drug use initiation age (OR = 0.918) was predicting drug cessation. Our result showed; family support is a more important effect among types of social support in drug cessation. It seems that providing educational program to addict’s families for more support of patients at drug cessation can be beneficial.

Keywords: drug cessation, family support, drug use, initiation age

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Authors: Temesgen Geremew

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Functionalized nanoparticles have emerged as a revolutionary platform for drug delivery, offering significant advantages over traditional methods. By strategically modifying their surface properties, these nanoparticles can be designed to target specific tissues and cells, significantly reducing off-target effects and enhancing therapeutic efficacy. This targeted approach allows for lower drug doses, minimizing systemic exposure and potential side effects. Additionally, functionalization enables controlled release of the encapsulated drug, improving drug stability and reducing the frequency of administration, leading to improved patient compliance. This work explores the immense potential of functionalized nanoparticles in revolutionizing drug delivery, addressing limitations associated with conventional therapies and paving the way for personalized medicine with precise and targeted treatment strategies.

Keywords: nanoparticles, drug, nanomaterials, applications

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Authors: Adegoke Yinka Adebayo

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An understanding of the critical product attributes that impact on in vivo performance is key to the production of safe and effective medicines. Thus, a key driver for our research is the development of new basic science and technology underpinning the development of new pharmaceutical products. Research includes the structure and properties of drugs and excipients, biopharmaceutical characterisation, pharmaceutical processing and technology and formulation and analysis.

Keywords: drug discovery, drug development, drug delivery

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Authors: Gail Louw, Helena Boshoff, Taeksun Song, Clifton Barry

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Drug resistance in Mycobacterium tuberculosis is primarily attributed to mutations in target genes. These mutations incur a fitness cost and result in bacterial generations that are less fit, which subsequently acquire compensatory mutations to restore fitness. We hypothesize that mutations in specific drug target genes influence bacterial metabolism and cellular function, which affects its ability to develop subsequent resistance to additional agents. We aim to determine whether the sequential acquisition of drug resistance and specific mutations in a well-defined clinical M. tuberculosis strain promotes or limits the development of additional resistance. In vitro mutants resistant to pretomanid, linezolid, moxifloxacin, rifampicin and kanamycin were generated from a pan-susceptible clinical strain from the Beijing lineage. The resistant phenotypes to the anti-TB agents were confirmed by the broth microdilution assay and genetic mutations were identified by targeted gene sequencing. Growth of mono-resistant mutants was done in enriched medium for 14 days to assess in vitro fitness. Double resistant mutants were generated against anti-TB drug combinations at concentrations 5x and 10x the minimum inhibitory concentration. Subsequently, mutation frequencies for these anti-TB drugs in the different mono-resistant backgrounds were determined. The initial level of resistance and the mutation frequencies observed for the mono-resistant mutants were comparable to those previously reported. Targeted gene sequencing revealed the presence of known and clinically relevant mutations in the mutants resistant to linezolid, rifampicin, kanamycin and moxifloxacin. Significant growth defects were observed for mutants grown under in vitro conditions compared to the sensitive progenitor. Mutation frequencies determination in the mono-resistant mutants revealed a significant increase in mutation frequency against rifampicin and kanamycin, but a significant decrease in mutation frequency against linezolid and sutezolid. This suggests that these mono-resistant mutants are more prone to develop resistance to rifampicin and kanamycin, but less prone to develop resistance against linezolid and sutezolid. Even though kanamycin and linezolid both inhibit protein synthesis, these compounds target different subunits of the ribosome, thereby leading to different outcomes in terms of fitness in the mutants with impaired cellular function. These observations showed that oxazolidinone treatment is instrumental in limiting the development of multi-drug resistance in M. tuberculosis in vitro.

Keywords: oxazolidinones, mutations, resistance, tuberculosis

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Authors: J. Oustric, L. Berti, J. Santini

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Nowadays, the objective of durable agriculture, and in particular organic agriculture, is to reduce the level of fertilizer inputs used in crops. Limiting the quantity of fertilizer inputs would optimize the economical result and minimizing the environmental impact. Nutrient deficiency, particularly of a major nutrient (N, P, and K), can seriously affect fruit production and quality. In citrus crops, rootstock/scion combinations. In citrus crop, scion/rootstock combinations are used frequently to improve tolerance to various abiotic stresses. New rootstocks are needed to respond to these constraints, and the use of new tetraploid rootstocks better adapted to lower nutrient intake could offer a promising way forward. The aim of this work was to determine whether a better tolerance to nutrient deficiency could be observed in a doubled diploid seedling and whether this tolerance could be observed in common clementine scion if used as rootstocks. We selected diploid (CM2x) and doubled diploid (CM4x) Citrumelo 4475 seedlings and common clementine (C) grafted onto Citrumelo 4475 diploid (C/CM2x) and doubled diploid (C/CM4x) rootstocks. Nutrient deficiency effects on the seedlings and scion/rootstock combinations were analyzed by studying anatomical, structural and ultrastructural determinants (chlorosis, stomata, ostiole and cells and their organelles), photosynthetic properties (leaf net photosynthetic rate (Pₙₑₜ), stomatal conductance (gₛ), chlorophyll a fluorescence (Fᵥ/Fₘ)) and oxidative marker (malondialdehyde). Nutrient deficiency affected differently foliar tissues, physiological parameters, and oxidative metabolism in leaves of seedlings depending on their ploidy level and of common clementine scion depending on their rootstocks ploidy level. Both CM4x and C/CM4x presented lower foliar damages (chlorosis, chloroplasts, mitochondria, and plastoglobuli), photosynthesis processes alteration (Pₙₑₜ, gₛ, and Fᵥ/Fₘ), and malondialdehyde accumulation than CM2x and C/CM2x after nutrient deficiency. Doubled diploid Citrumelo 4475 can improve nutrient deficiency tolerance, and its use as a rootstock allows to confer this tolerance to the common clementine scion.

Keywords: nutrient deficiency, oxidative stress, photosynthesis, polyploid rootstocks

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Authors: S. Niamkaeo, O. Robert, O. Chaowalit

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In this investigation, we focus on discovering spatial relationship of drug smuggling along the northern border of Thailand. Thailand is no longer a drug production site, but Thailand is still one of the major drug trafficking hubs due to its topographic characteristics facilitating drug smuggling from neighboring countries. Our study areas cover three districts (Mae-jan, Mae-fahluang, and Mae-sai) in Chiangrai city and four districts (Chiangdao, Mae-eye, Chaiprakarn, and Wienghang) in Chiangmai city where drug smuggling of methamphetamine crystal and amphetamine occurs mostly. The data on drug smuggling incidents from 2011 to 2017 was collected from several national and local published news. Geo-spatial drug smuggling database was prepared. Decision tree algorithm was applied in order to discover the spatial relationship of factors related to drug smuggling, which was converted into rules using rule-based system. The factors including land use type, smuggling route, season and distance within 500 meters from check points were found that they were related to drug smuggling in terms of rules-based relationship. It was illustrated that drug smuggling was occurred mostly in forest area in winter. Drug smuggling exhibited was discovered mainly along topographic road where check points were not reachable. This spatial relationship of drug smuggling could support the Thai Office of Narcotics Control Board in surveillance drug smuggling.

Keywords: decision tree, drug smuggling, Geographic Information System, GIS knowledge discovery, rule-based system

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Authors: Meena Kumari, Ajitha Sharma, Mohan Babu Amberkar, Hasitha Manohar, Joseph Thomas, K. L. Bairy

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Aim: To evaluate the pattern of occurrence of adverse drug reactions (ADRs) with platinum compounds in cancer chemotherapy at a tertiary care hospital. Methods: It was a retrospective, descriptive case record study done on patients admitted to the medical oncology ward of Kasturba Hospital, Manipal from July to November 2012. Inclusion criteria comprised of patients of both sexes and all ages diagnosed with cancer and were on platinum compounds, who developed at least one adverse drug reaction during or after the treatment period. CDSCO proforma was used for reporting ADRs. Causality was assessed using Naranjo Algorithm. Results: A total of 65 patients was included in the study. Females comprised of 67.69% and rest males. Around 49.23% of the ADRs were seen in the age group of 41-60 years, followed by 20 % in 21-40 years, 18.46% in patients over 60 years and 12.31% in 1-20 years age group. The anticancer agents which caused adverse drug reactions in our study were carboplatin (41.54%), cisplatin (36.92%) and oxaliplatin (21.54%). Most common adverse drug reactions observed were oral candidiasis (21.53%), vomiting (16.92%), anaemia (12.3%), diarrhoea (12.3%) and febrile neutropenia (0.08%). The results of the causality assessment of most of the cases were probable. Conclusion: The adverse effect of chemotherapeutic agents is a matter of concern in the pharmacological management of cancer as it affects the quality of life of patients. This information would be useful in identifying and minimizing preventable adverse drug reactions while generally enhancing the knowledge of the prescribers to deal with these adverse drug reactions more efficiently.

Keywords: adverse drug reactions, platinum compounds, cancer, chemotherapy

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Authors: Afsaneh Ghorbanzadeh, Afshin Farahbakhsh, Zakieh Bayat

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The drug capsulation was used for release and targeted delivery in determined time, place and temperature or pH. The DOX nanocapsules were used to reduce and to minimize the unwanted side effects of drug. In this paper, the encapsulation methods of doxorubicin (DOX) and the labeling it by the magnetic core of iron (Fe3O4) has been studied. The Fe3O4 was conjugated with DOX via hydrazine bond. The solution was capsuled by the sensitive polymer of heat or pH such as chitosan-g-poly (N-isopropylacrylamide-co-N,N-dimethylacrylamide), dextran-g-poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) and mPEG-G2.5 PAMAM by hydrazine bond. The drug release was very slow at temperatures lower than 380°C. There was a rapid and controlled drug release at temperatures higher than 380°C. According to experiments, the use mPEG-G2.5PAMAM is the best method of DOX nanocapsules synthesis, because in this method, the drug delivery time to certain place is lower than other methods and the percentage of released drug is higher. The synthesized magnetic carrier system has potential applications in magnetic drug-targeting delivery and magnetic resonance imaging.

Keywords: drug carrier, drug release, doxorubicin, iron oxide NPs

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Authors: Maryam Beiranvand

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Multi-drug resistance in various microorganisms has increased globally in many healthcare facilities. Less effective antimicrobial activity of drug therapies for infection control becomes trouble. Since 1980, no new type of antimicrobial drug has been identified, even though combinations of antibiotic drugs have been discovered almost every decade. Between 1981 and 2006, over 70% of novel pharmaceuticals and chemical agents came from natural sources. Microorganisms have yielded almost 22,000 natural compounds. The identification of antimicrobial components from endophytes bacteria could help overcome the threat posed by multi-drug resistant strains. The project aims to analyze and identify antimicrobial peptides isolated from entophytic bacteria and their activity against multidrug-resistant Gram-negative bacteria in South Korea. Endophytic Paenibacillus polymyxa. 4G3 isolated from the plant, Gynura procumbery exhibited considerable antimicrobial activity against Methicillin-resistant Staphylococcus aureus, and Escherichia coli. The Rapid Annotations using Subsystems Technology showed that the total size of the draft genome was 5,739,603bp, containing 5178 genes with 45.8% G+C content. Genome annotation using antiSMASH version 6.0.0 was performed, which predicted the most common types of non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS). In this study, diethyl aminoethyl cellulose (DEAEC) resin was used as the first step in purifying for unknown peptides, and then the target protein was identified using hydrophilic and hydrophobic solutions, optimal pH, and step-by-step tests for antimicrobial activity. This crude was subjected to C18 chromatography and elution with 0, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 100% methanol, respectively. Only the fraction eluted with 20% -60% methanol demonstrated good antimicrobial activity against MDR E. coli. The concentration of the active fragment was measured by the Brad-ford test, and Protein A280 - Thermo Fisher Scientific at the end by examining the SDS PAGE Resolving Gel, 10% Acrylamide and purity were confirmed. Our study showed that, based on the combined results of the analysis and purification. P polymyxa. 4G3 has a high potential exists for producing novel functions of polymyxin E and bacitracin against bacterial pathogens.

Keywords: endophytic bacteria, antimicrobial activity, antimicrobial peptide, whole genome sequencing analysis, multi -drug resistance gram negative bacteria

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