Pharmaceutical Sciences العلوم الصيدلانية

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Antibacterial activity of Novel Prodrugs of Amoxicillin and Cephalexin
(AL-Quds University, 2015-06-02) ساميه صلاح الدين عبد الغني كرد; samia salahaldeen abdalgani kord; رفيق قرمان; احمد عمرو; حاتم سلامة
The two novel prodrugs of amoxicillin and cephalexin were synthesized to improve the stability and bitter taste of their parent drugs. The in vitro susceptibility for both prodrugs was determined against Escherichia coli, staphylococcus epidermidis, staphylococcus aureus, Klebsiella pneumonia, streptococcus group A, streptococcus group B, and compared to that of their parents. The results revealed that both novel prodrugs have antibacterial activity on most bacterial strains with about the same potency as their parent drugs, In addition, Klebsiella pneumonia, and staphylococcus epidermidis showed resistance to both amoxicillin drug and its prodrug. Since klebsiella is gram negative bacteria and staphylococcus epidermidise is beta lactamase positive . It is worth noting that those two novel prodrugs are among a small number of prodrugs that have activity themselves before undergoing conversion via enzymatic or chemical processes to their corresponding parent drugs. The novel prodrugs exhibit their antibacterial activity against different types of bacterial strains due to the presence of beta lactam ring in their structures. In addition, it is expected that the novel two prodrugs will be much more stable in aqueous media than their corresponding parent drugs due to the fact that the sensitive amine group exists in the parent drugs was replaced with a more stable group, amide.
Antibiotics Dispensing Patterns in The Community Pharmacies in Gaza Governorate
(Al-Quds University, 2008-03-01) Mostafa Omar El-Ghosain; مصطفى عمر الغصين
Anticancer, Antioxidant, Antimicrobial, and Enzymes Inhibitory Effects of Terfezia Arenaria from Palestine
(Al-Quds University, 2023-04-29) Ahmed Mutasem Tawfiq Alkhader; أحمد معتصم توفيق الخضر
Terfezia arenaria belongs to the Terfeziaceae truffle family and is one of the most important desert truffles in Palestine. It is an edible truffle with many medicinal folks uses in the past and present, so the study was designed to consolidate knowledge about this truffle and to validate the medicinal uses of the natural products. In the beginning, we used a variety of extraction methods including Soxhlet extraction, sonication extraction, and exhaustive extraction, as well as various solvents with varying polarity properties including methanol, ethanol, water, acetone, hexane, dichloromethane and ethyl acetate. We relied on sonication extraction with methanol as a solvent because it yielded the highest extract, whereas other solvents yielded negligible amounts of extract. Qualitative tests were performed to investigate the ingredients of the methanolic extract, which revealed the presence of flavonoids, phenols, glycosides, carbohydrates, and steroids. The flavonoids and phenolic compounds were then determined quantitatively, using Folin-Ciocalteu’s method for phenolic contents and aluminum chloride method for flavonoids. This work also investigated the expected effect of these compounds in addition to the discovery of new effects of the T. arenaria. We tested the enzyme inhibition effect on amylase enzyme, which is naturally present in the human intestine and plays an important role in carbohydrates digestion; inhibiting the enzyme may be useful to reduce the absorbed amount of glucose and thus improve the treatment of diabetic patients, so we measure the absorbance using UV spectrophotometer and higher absorbance means higher inhibition, and we use acarbose which is an antidiabetic drug as a positive control. The other enzyme we tested for inhibition effect is lipase enzyme, which is found normally in humans and other mammals and digests lipids, so inhibiting it may also aid in the treatment of obesity, orlistat used as a reference in this test and using UV spectrophotometer same as amylase inhibition. Another important test we carried was the extraction of antioxidant because oxidative stress is a factor in the progression of many diseases, and a positive antioxidation effect may be beneficial in reducing Alzheimer, dementia, cancer, and many other diseases. In our study we used reducing power assay method to determine the antioxidant activity. The antibacterial activity was tested on different bacterial species, gram-positive and gram-negative bacteria, to validate one of the most well-known uses. Cytotoxicity activity was also investigated in order to test the ability to treat cancer cells in vitro, and two different cell lines used, which could be the first step in the discovery of a new lead compound for cancer therapy. In our results we found our desert truffle to have various biochemical compound and good phenolic and flavonoids contents, so this will have positive impact on our results. And also, the results of enzymes inhibition activity were good enough to build on, as it showed good inhibition comparatively with the positive controls. For the anticancer activity there was obvious cell growth inhibition on two different cell lines used, while there was no antibacterial activity.
Assesment of Beliefs about Medicines and Adherence among Patients withSchizophrenia at the Primary Care Unit in Ramallah, Palestine
(Al-Quds University, 2020-06-06) Aroub Salman Mohammad Salman; عروب سلمان محمد سلمان
Objectives and background: Schizophrenia is a serious mental illness that needs more attention to be paid for. It affects how patients think, feel and behave. The exact causes underlying the problem is still unknown, but a number of risk factors can be identified including genes and environment. The aims of this study were to assess medication adherence to antipsychotic medications and to measure patients’ beliefs about their treatment necessities and concerns, which contribute to their antipsychotics adherence and treatment efficacy.Methodology: One hundred and thirty patients were recruited from the governmental psychiatry clinic in Ramallah in a cross sectional study. The self-reported Morisky-Green-Levine (MGL) scale was used to measure patients’ adherence. Beliefs about medicines questionnaire (BMQ) was used to measure beliefs about medicines.Results: The result in this study indicated that 53.8 % of the sample participants were classified as low-adherent while 46.2% of patients classified as high adherent. The majority of the patients (66.3%) had strong beliefs and necessity in their medications to maintain their good health, more than half of patients (55.4%) were concerned about becoming dependent upon antipsychotics and long-term side effects. The mean score of specific necessity scale of 16.9 (CI 95%, 15.9 - 17.9) and mean score of specific concerns scale of 16.5 (CI 95%, 15.4 - 17.6; P<0.001) were significantly correlated to medication adherence, and the mean of necessity–concern differential was 2.1 (CI 95%, 2.5 – 1.7; p <0.11) . (Extended) Brief .Psychiatric Rating Scale BPRS domains mean scores were: manic 21.4 ± 8.8, depression and anxiety 20.3 ± 6.2, negative symptoms 13.8 ± 4.6 and positive symptoms 17.7 ± 6.3. BPRS mean score was 77.1± 24.9. The multivariate regression model demonstrated that four variables remain significant and associated with non-adherence; no formal education (OR= 2.11; CI: 0.8 – 3.8) (p=0.04), age (OR= 2.88; CI: 1.2 – 4.4) (p = 0.01), having comorbidity (OR= 3.2; CI: 1.9 – 4.3) (p=0.01) and having concerns about side effects (OR= 2.5; CI: 1.2 – 3.9) (p = 0.03); as they are positively correlated to non-adherence.Conclusion: More than half of participants in this study had low adherence to their antipsychotic agents. Most of patients had strong beliefs in the necessity to use their medications. However, high percentage of the patients had concerns about long-term and potential side effects of antipsychotic medications. Therefore, our role as pharmacist is raising patients’ awareness and beliefs about medications for better treatment outcomes; by educating them about anti-psychotics, their adverse events and conducting several interventions regarding patient compliance.
Assessing Quality of life of Cystic Fibrosis patients in West Bank and New Therapeutic Options
(AL-Quds University, 2017-10-07) ساميه عزت محمد صلاح; Samya Izat Mohammed Salah; ماهر الخضور; Dr. Hussein Hallak; Ghassan Balousha; Waleed Sweileh
Background The number of cystic fibrosis patients is increasing around the world, Latest forecasts published in the European Respiratory Journal indicate an increase of approximately 50% by 2025 (20% in the child population; 75% in the adult population). There is no accurate epidemiological data on CF disease in Palestine. The general impression has been that the disease is rare, but this is most likely the result of underdiagnosis or misdiagnosis due to limited awareness of the condition in the region. This disease has high treatment burden and some of the novel technology used for drug delivery is highly beneficial because it may ease patient burden by decreasing administration time and offer more efficacy and safety. These options are not available for CF patients in Palestine, only basic traditional therapies are available and this is the fundamental problem. Assessment of the patient's perspective of symptom improvement, satisfaction and their reported increase in health related quality of life (HRQoL) should be part of the treatment decision making. Most of the cystic fibrosis patients QoL studies have been conducted in developed countries and only a few in developing countries but no studies were done in Palestine. Objective The purpose of this project was to study the Palestinian health situation by using specific comparison tools including; Quality of life issues of Palestinian CF patients attending the Caritas baby hospital, their health status, their related cost effective treatment (Economical burden) and summarize the available evidence on the use of new options for the treatment by using a willingness to pay survey. MethodA descriptive narrative study conducted for patients from West Bank suffering from cystic fibrosis disease. These patients used basic classic therapies and attending pediatric pulmonology clinic in Caritas Baby Hospital. Around 77 participants completed four quantitative assessment measures and provided demographic information. The status of CF patients were studied by using different aspect. Their quality of life score using CFQ-R questionnaire were measured. Their health status were screened by measuring different parameter; pulmonary function test, body mass index, their age at diagnosis and mortality rate related to CF disease. Their health related cost and the amount of money they are able to pay for improving their treatment options using a willingness to pay survey were calculated. Caritas Baby Hospital (CBH) Medical Research Committee/Ethical Review Board approved this study and a written informed consents form for the patients and their families were obtained. Results were analyzed using scoring software and SPSS softwareResults and conclusion The overall score for CF patients QoL parameters is less than 60% (ranges from 14.5- 55.6) which indicate poor quality of life relative to other countries worldwide. The lowest score is for body (14.5), treatment (17.5), and respiratory (27.5). The highest score appears to be for eat (55.6) and emotion (50). Illness severity as measured by FEV1 percent predicted with mean value of 69.6%. BMI recorded with mean value 15.998 (Kg/m2 ). With the overall mean age at diagnosis in our sample was 4.16 years of age. The study showed that 58.3% (7/12) of patients from Hebron district had high mortality rate related to CF disease. The result revealed that quality of life for CF patients is influenced by age, gender, taking vacation without disease, work or school status, BMI measures, age at diagnosis for the patient's parameters. In addition, QoL as scored by their parents parameter which included: the age, educational level and work status of both parents and is also affected by total number of CF patients in each family. QoL for CF patients is not influenced by marital status, geographic distribution, place of residency (city, village and camp), FEV1 measures, willingness to pay answers, their parent's relationship (father or mother), monthly income, and the effect of taking influenza vaccine yearly. For willingness to pay, results indicate that 93.5% said yes and 6.5% said no. 51.4% of patients are able to pay 100 NIS out of pocket to 2.7% able to pay 2000 NIS or more out of pocket to get new drugs. With economical evaluation for CF patient, the total costs for patient with the mean age of our sample 10.7 years of age were estimated to be around 35650.2 NIS per patient per year. Cost reduction were estimated after applying Dornase-alfa as a mucolytic drug and Tobramycin nebulizer solution. This added value can help in part of the cost for making these drugs available for CF patients in our region. Overall, quality of life for patients with CF is poor relative to international standards, the medications used including Hypertonic saline and Gentamycin IV form used asnebulizer solution are not first line therapies around the world, patients and their families demand better treatment and are willing to pay to get better treatment. Now we have an objective proof to submit for the need of new therapies for CF patients in Palestine in order to improve their QoL, health status and longevity .
Assessment of Patient’s Satisfaction with Pharmaceutical Care Services in Community Pharmacies in west bank: A cross sectional study
(Al-Quds University, 2023-05-20) Sujood Theab Nemer Mashaala; سجود ذياب نمر مشاعلة
The provision of pharmaceutical services to the community and the care of patients are significant responsibilities of pharmacists. It is unclear if the general public completely understands the important role that pharmacists play in the healthcare system. This study aim was to examine general public perception about community pharmacy services, and how satisfied they are with pharmaceutical care services utilizing the health beliefs model (HBM).Methods A cross-sectional study was carried out on a randomly chosen sample population (n = 400) in West Bank from January through June 2022 for a period of six months. A standardized, self-administered questionnaire with 35 items was used to gather information on the respondents' demographics and satisfaction with pharmacy services utilizing (HBM). Results:The response rate of the survey was 87%. The majority of the respondents perceived benefit of utilizing pharmaceutical care services with mean score (24.5 ± 4.6). There was a significant differences between mean perceived benefit and perceived barriers (24.5 vs. 17.5, p <0.05). Participants generally did not express a high level of agreement on the four susceptibility-assessing items (mean = 11.55 ± 2.44, range 4-20). However, the four questions measuring perceived severity had better agreement (mean = 13.3 ± 3.0, range 4-20). The participants express modest satisfaction with pharmaceutical services and managing therapy, the mean (± SD) score on the satisfaction scale was (24.1±7.1, range 10 - 50). The items regarding lack of privacy and explain side effects of drugs had the highest dissatisfaction percentages (91% and 55%, respectively). Multiple linear regression demonstrated four variables to be significantly correlated with satisfaction with pharmaceutical care services included perceived susceptibility (β = .157, p = .002), residency (β = -.203, p = 0.001), number of medications (β = -.237, p = .001), and perceived barriers (β = -.132, p = .012). Indicating, that participants with higher number of medication and those perceived susceptibility were more satisfied and those perceived barriers were less satisfied with pharmaceutical care provided by community pharmacies. Conclusion: The majority of the participants express modest satisfaction with pharmaceutical care services. The community pharmacists in ideal position to and have the ability to improve the benefit patients perceive by providing comprehensive pharmaceutical care services and managing medication therapy.
Beliefs about cholesterol lowering drugs and medication adherence among Palestinian adults with dyslipidemia in Ramallah and Bethlehem areas of the West Bank
(AL-Quds University, 2019-12-07) جهاد خليل احمد شكارنه; JIHAD KHALIL AHMAD SHAKARNA; حسين الحلاق; aher Khdour; Samah Al-Jabi
Design and Synthesis of Trisubstituted Pyrimidine Derivatives as Coactivator Binding Inhibitors (CBIs) of Estrogen Receptor Signaling
(AL-Quds University, 2016-01-09) ميران محمد جمال طلال مسودى; Miran M.Jamal Talal Masswadeh; يوسف نجاجرة; Zaidoun Salah; Tawfeq Kaimari
Breast cancer (BC) is one of the most commonly diagnosed cancers in women. Estrogen signaling and the estrogen receptors (ERα, ERβ) are implicated in breast cancer progression. Majority of breast cancers start out as estrogen dependent as a result of overexpression of ER-regulated genes: Estrogen deprivation therapy using anti-estrogens (AEs) and aromatase inhibitors (AIs) to block ER activity and arrest the estrogen-dependent growth of BC still represents the primary treatment for breast cancer patients. This approach, however, frequently fails and patients develop resistant breast cancer, which is almost untreatable. In this project we focused on synthesizing a potent coactivator binding inhibitors (CBIs) molecules that block ER activity through a different mechanism that may arrest the estrogen-dependent growth of BC and offer a solution to the existing resistance. Coactivator binding inhibitors (CBIs) act by blocking the conformational change needed for DNA binding and gene expression. In this project set of compounds have been designed, synthesized through sequential substitution of the chlorine atoms of 2,4,6-trichloropyrimidine with amines or other nucleophiles. The synthesized compounds were purified using chromatography techniques, and characterized by (1H-NMR, 13C-NMR, FT-IR and MS (ESI)) spectroscopy. Some of these compounds were screened for their inhibitory activity against the acute myeloid leukemia cells (Molm-13) cells. Two forms of Molm-13 had been used to evaluate the role of p53. In one case cells were transfected with empty vector and in the other the cells were tranfected with sh-p53 RNA(sh-p53). The viability of cells was determined using WST-1 assay. Initial results of the tested compounds demonstrated that MY12 (35) and MY3 (26) exhibited potent activities against the two forms of Molm-13 cell lines and have a dose dependent effect while the compound MY2 (25) showed no significant inhibitory action on the same cell lines.
Design of Novel 6-Aminocaproic acid Prodrugs by Computational Methods
(AL-Quds University, 2017-08-26) نداء مازن سالم لقيانية; neda mazen salem leqeanea; رفيق قرمان; Dr. Hatem Hejaz; : Dr. Naser Shraim
Background and objectives: Unraveling the mechanisms of a number of enzyme models has allowed for the design of efficient chemical devices having the potential to be utilized as prodrug linkers that can be covalently attached to commonly used drugs which can chemically, and not enzymatically, be converted to release the active drug in a programmable manner. For instance, exploring the mechanism for a proton transfer in Kirby‘s N-alkylmaleamic acids (enzyme model) has led to the design of a number of prodrugs such as tranexamic acid, acyclovir, atenolol. Method: Based on density functional theory (DFT) calculations for the acid-catalyzed hydrolysis of several N-alkylmaleamic acid derivatives five 6-aminocapproic acid prodrugs were designed, aiming to provide a drug with potentially to have higher bioavailability than its parent drug. Result and discussion: DFT calculations at B3LYP/6-31G(d,p) for intramolecular proton transfer in 1-7 and prodrugs of 6-aminocapproic acid, ProD1-ProD5, demonstrated that the reaction rate is dependent on the strain energy difference between the intermediate and the reactant (Es INT-GM). This suggests that the reaction is governed by strain effect. Additionally, no correlation was found between the proton transfer efficiency and the distance between the two reactive centers (rGM) and the attack angle (α). Conclusion: Hence, the rate by which the prodrug releases the 6-aminocapproic acid drug can be determined according to the structural features of the promoiety (Kirby’s enzyme model)
Design of Novel Amoxicillin Prodrugs by Computational Methods
(AL-Quds University, 2017-07-26) وعد محمد صالح حوراني; waad mohammad saleh huorani; رفيق قرمان; Dr.Hatem Hejaz; Dr.naser shraim
Design of Novel Dopamine Prodrugs - A Computational Approach
(AL-Quds University, 2017-12-04) إسراء تيسير محمد قطوش; رفيق قرمان; Dr. Hatem Hejaz; Dr. Naser Shraim
Design of Novel Dopamine Prodrugs - A Computational Approach
(AL-Quds University, 2018-08-18) إسراء تيسير محمد قطوش; Essra tayseer mohammad qattoush; رفيق قرمان; Dr. Hatem Hejaz; Dr. Naser Shraim
Parkinson patients have insufficient dopamine in specific regions of the brain, so attempts have been made to replenish the deficiency in the dopamine. Dopamine itself doesn't cross blood brain barrier, but its precursor, levodopa (LD) is actively transported into the CNS and is converted to dopamine in the brain. The bioavailability of LD is less than 10% with only 1% of administered oral levodopa penetrates the brain. Large doses of levodopa are required because much of the drug is decarboxylated to dopamine in the periphery, resulting in side effects that include nausea, vomiting, cardiac arrhythmias, and hypotension. To minimize the conversion to dopamine (DA) outside the central nervous system (CNS), LD is usually co-administered with peripheral inhibitors of amino acid decarboxylase (carbidopa or benserazide). In spite of that, other central nervous side effects such as dyskinesia, on-off phenomenon and end-of-dose deterioration still remain. In this project, a number of dopamine prodrugs were designed using DFT molecular orbital at B3LYP 6-31G (d, p) levels and molecular mechanics (MM2) calculations aiming to provide prodrugs that are expected to give better bioavailability than the parental drug owing to improved absorption. Furthermore, the proposed prodrugs are believed to be more effective than L-dopa because the latter undergoes decarboxylation in the periphery before reaching the blood–brain barrier. The DFT calculation results revealed that the rate of a proton transfer in processes dopamine ProD 1-ProD 5 is largely dependent on the geometric variations of thereactant (GM) mainly the distance between the two reactive centers, rGM, and the angle of attack α. It was found that systems with low rGM and high α values in their global minimum structures, such as ProD 1 and ProD 2, exhibit much higher rates (lower ∆G‡ ) than these with high rGM and low α values, such as ProD 3-ProD 5 and the rate of the reaction is linearly correlated with rGM and (1/α). Moreover, it was found that the intraconversion rate of the designed dopamine prodrugs is largely determined on the strain energies of the reaction ̓s tetrahedral intermediates(EsINT). Systems having strained tetrahedral intermediates were found to be with low rates and vice versa.
Design of Novel Gabapentin Prodrugs by Computational Methods
(AL-Quds University, 2021-01-05) هنادي عبد الكريم حسني سنقرط; Hanadi A H Sunoqrot; رفيق قرمان; صالح جبور; حاتم حجاز
Design of Novel Phenylephrine and Paracetamol Prodrugs by Computational Methods
(AL-Quds University, 2016-01-05) دنيا ابراهيم خالد قرمان; donia ibrahim khalid karaman; رفيق كرمان; Omer Deeb; Nasr Shraim
Design of Novel Raloxifene Prodrugs by Computational Methods
(Al-Quds University, 2021-12-22) Nermeen Nader Ibrahim Hajjaj; نيرمين نادر إبراهيم حجاج
A number of Kirby ̓s enzyme models for six Raloxifene prodrugs on both sides (left and right sides) are designed based on molecular orbital of DFT at B3LYP 6-31G (d, p) level and molecular mechanics (MM2) calculations of the intramolecular proton transfer which run in the gas and water phase for right side and in the gas phase for left side to provide a medicine of controlled release for Raloxifene to enhance the bioavailability than its parent drug. Results proves thatRaloxifene ProD1-ProD6processes on two sides aremajor affected and depended on two factors of the global minimum (GM) which includes the distance between the two reactive centers, rGM, and the angle of attack α that also affected on the rate of a proton transfer for Raloxifene where lower ∆G‡(higher rates) refer to system of low rGM and high α values for example ProD4 andProD6at left side and ProD5 and ProD6at right sidealso, the system of higher∆G‡(lower rates) refer to high rGM and low α values, for example (ProD1, ProD2,ProD3, ProD5) at leftand (ProD1, ProD2,ProD3, ProD4) at right.Thus, it is recommended that RaloxifeneProD4,ProD6 at left side and ProD5 and ProD6 at right side shouldbe entered and tested in vitro and in vivotrials steps of synthesis. Moreover, it was found that the internal conversion rate of Raloxifene prodrugs is significantly affected by the strain energy of each value which refers to the difference between the strain energy of tetrahedral intermediate and the reactant, since the higher the strain the lower the internal conversion rate, and vice versa. تم إنجاز هذه الأطروحة باستخدام المدار الجزيئي DFT عند مستوىB3LYP 6-31G (d, p) وحسابات الميكانيكا الجزيئية (MM2) لنقل البروتون داخل الجزيء في عدد من نماذج إنزيم Kirby لتصميم العقاقير الأولية من الرالوكسيفينعلى الجانبين (اليسار واليمين). لتوفير دواء لديه القدرة على إطلاق للرالوكسيفين بطريقة قابلة للبرمجة والتحكم مع توافر بيولوجي أعلى من الدواء الأصلي. هناك ستة عقاقير أولية من رالوكسيفين على الجانبين (الجانب الأيسر والأيمن) تم تصميمها اعتمادًا على نموذج إنزيم نقل البروتون في كيربي. بطريقة DFT عند B3LYP / 6-31G (d,p)تم إجراء حسابات مستوى في الطور الغازي وفي ثابت العزل الكهربائي 79.38 (طور الماء) للجانب الأيمن وفي الطور الغازي للجانب الأيسر. تم الكشف عن أن معدل نقل البروتون في عمليات ProD1-ProD6الرالوكسيفينعلى الجانبين يعتمد إلى حد كبير على الاختلافات الهندسية للمتفاعل (GM) بشكل أساسي المسافة بين المركزين المتفاعلين(rGM) وزاوية الهجوم (α). لاستنتاج أن الأنظمة التي تحتوي على قيم rGM منخفضة وقيم α عالية في هياكلها الدنيا العالمية ، مثلProD4 و ProD6 في الجانب الأيسر ProD5 و ProD6 في الجانب الأيمن تظهر معدلات أعلى بكثير (أقل G ‡) من هذه مع قيم rGM عالية وقيم α منخفضة ، مثل ProD1 و ProD2وProD3 و ProD5 على اليسار ProD1وProD2 وProD3وProD4 على الجانب الأيمن. وبالتالي ، فمن المستحسن أن الرالوكسيفين ProD4 و ProD6 في الجانب الأيسر و ProD5 و ProD6 على الجانب الأيمن يجب أن تسبق الاختبار في المختبر وفي الجسم الحي. علاوة على ذلك،لقد وجد أن معدل التحويل الداخلي للرالوكسيفينprodrug يتأثر بشكل كبير بقوة strainلكل من رباعية الاسطوح المتوسطة، حيث ان من تملك strain اعلى يكون معدل التحويل الداخلي أقل ، والعكس صحيح.
Design of Novel Tranexamic acid Prodrugs by Computational Methods
(AL-Quds University, 2017-12-07) مريم مأمون محمد بدر; BADER MOHAMMED MAMOUN MARIAM; رفيق قرمان; Saleh Jbour; Hatem Hejaz
Design, Synthesis and Cytotoxic Activity of Novel 2,3-disubstituted Pyrazine Derivatives
(AL-Quds University, 2017-12-06) آلاء محمود ربيع فرعون; Ala Mahmoud Rabie Faroun; يوسف نجاجرة; imad odeh; Michel Hanania
Pyrazine derivatives possess numerous pharmacological effects including but not limited to antiviral, antibiotic, antifungal, diuretic, anticonvulsant, antidiabetic, analgesic and anti proliferative effect. Consequently, interest has been shown by researchers in the field of pyrazine-based drug synthesis and many of the synthesized derivatives succeeded to reach the clinical field. A promising research discipline was concerned in utilizing the antiproliferative and cytotoxic activity of pyrazine derivatives -that is attributed to various mechanisms one of which is protein kinase inhibition- in designing new anti-cancer agents. In this study a set of disubstituted pyrazine derivatives has been designed and synthesized through a sequential nucleophilic substitution of chlorine atoms of 2,3-dichloropyrazine with amines or other nucleophiles. The synthesized derivatives were purified using several chromatographic techniques, and characterized by (1H-NMR, 13C-NMR, FT-IR, and MS (ESI)) spectroscopy. The mono-substituted pyrazine derivative A-7 (7) and three of its disubstituted analogues (YAN1(18), YAN-2 (19), and YAN-3(20)) were in vitro screened for their biological activity against two forms of acute myeloid leukemia cells (Molm-13). The viability of the cells was determined using WST-1 assay. Initial results of the tested derivatives showed that A-7 (7) was more potent than its analogues with IC50 of 18 and 39 µM against Molm-13 (sh-p53) and Molm-13 (empty vector) respectivelyThe biological activity of mono and disubstituted pyrazine derivatives was predicted using PASS software. Initial results demonstrated that A13 (13), A14 (14), YAN-7 (24), and YAN-8 (25) exhibited predicted activities as antineoplastic agents and signal transduction pathway inhibitors with relatively high Pa values. The previously mentioned compounds shared also the same mechanism of action “protein kinase inhibitor” with Pa values larger than 0.8SAR derived from PASS and initial biological activity screening results proved that the activity of the synthesized derivative is highly affected by the site and type of the substituent on the pyrazine ring. 2,3-disubstituted derivatives showed better Pa values when compared to the corresponding 2,5-disubstituted ones. In addition, amine substituents at positions 2 and 3 of pyrazine ring were preferred over alkoxide substituents in terms of antineoplastic activity. It was noticed that 1-(5-trifluoromethylpyridin-2-yl)-piperazine and 2-aminopyridine pharmacophores were the most active amine substituents. In order to gain an insight into the binding mode of pyrazine derivatives with CDK-2, a series of sixteen derivatives were docked with inactive monomeric cyclin dependent kinase-2 using SwissDock software. Results were compared with ‘Aloisine B‟, a well-known CDK-2 inhibitor. In terms of binding mode, pyrazine derivatives occupied the CDK-2 ATP binding site and made hydrogen bonds to the kinase backbone within the hinge sequence that links the two lobes of the kinase. The docked derivatives exhibited different binding affinities to the target, YAN-8 (25) showed the highest full fitness value (-1422.14 kcal/mol) among the synthesized derivatives. Moreover, both the full fitness and energy values indicated that YAN-8 (25) has higher affinity to the target in comparison to the known inhibitor Aloisine B (-1406.92 kcal/mol). Finally, the concept of drug likeness of the synthesized derivatives was investigated using the rule of five. Results revealed that all of the tested derivatives successfully met the rule of 5requirements except YAN-9 (26) and YAN-10 (27) which possessed molecular weights larger than 500 Daltons..
EEffect of Pharmaceutical Marketing Practice on Physicians’ Prescribing Behavior in the Gaza Strip
(Al-Quds University, 2021-06-10) Rafat Subhi Abd Elftah Aburedwan; رأفت صبحي عبد الفتاح أبو رضوان
Pharmaceutical Companies (PCs) are using different marketing activities to influence physicians’ prescribing behavior. However, the interaction between physicians and PCs is a real leading factor for conflicts of interest that negatively impact physician prescribing behaviors worldwide. The aim of this study is to identify the effect of pharmaceutical marketing practice on physicians’ prescribing behavior in the Gaza Strip (GS). To fulfill the aim of the study, the researcher followed a mixed approach that utilizes quantitative and qualitative data. For quantitative data, a cross-sectional, descriptive-analytical survey was utilized among specialist physicians working in the governmental hospitals as well as the private hospitals and clinics in the GS in 2020. A self-administered well-structured questionnaire was used. For the qualitative part, focus groups and in-depth interviews were used for data collection from physicians, pharmacists, and pharmaceutical medical representatives (PMRs). Data were analyzed using SPSS. The questionnaire response rate is 91.3% (347 returned questionnaires) was achieved. This study revealed that many physicians prefer the internet (82.4%) the medical, textbooks (80.2%), and academic journals (74%) as sources of drug information rather than commercial sources of medical information However, nearly (64.2%) of physicians depend on detailing as a source of drug information. Also, 70.8%, 68.6% of physicians agreed on the importance and credibility of information provided through PMRs about the new and old drugs respectively. Results highlighted the complex correlated factors that impact physicians’ prescription behavior. These factors were categorized into drug characteristics (80.1%), organizational factors (79.1%), physician factors (75.8%), patient contexts (69.3%), and the least influential factor was pharmaceutical company factors (59.9%). However, results showed that there is an active interaction between physicians and the PCs. Findings revealed that 96% of the study sample had been visited by PMRs at least once a month. Almost all of the physicians (98.3%) received at least one of the marketing tools offered by (PCs). PMRs detailing has become prevalent in health facilities in the GS with 96.2% of physicians received skillful detailing. The provision of promotional printed material (95.7%), free medical samples (93.9%), and inexpensive gifts (74.6%) were the major prescribing inducement tools used by PMRs. The study results revealed that the current marketing tools have a considerable effect on drug choice decisions (64.2%), motivating physicians to prescribe promoted drugs (65.2%) and new drugs (66.8%). However, the influence of these tools was not similar in their effect. The most effective tools used were detailing and discussions with PMRs (73.4%). The following characteristics were significantly associated with the effect of pharmaceutical marketing on physicians’ prescription behavior: age, years of practice, average monthly income, income satisfaction, graduation country of bachelor. Also, results confirm that physicians (61.73%) are prepared to implement regulations and ethical codes that govern physicians – PMRs interactions. In conclusion, there is an active interaction between physicians and the pharmaceutical industry in the GS in both private and public sectors. These interactions had a considerable role in affecting physicians’ prescription behavior. An agreed drug prescribing policy, as well as a comprehensive guideline for physicians’ interactions with pharmaceutical companies along with follow-up mechanisms for its enforcement, should be created. Also, should promote the concept of essential drug list of medicines and developing clear protocols and guidelines and applying them. Also establish comprehensive formal training courses for physicians on their prescribing behavior. Promoting the concept of rational use of medicines and developing protocols and guidelines and enforcing them.
The Efficiency of FLAIR-Weighted BLADE in image Quality Parameter Correction for Moved Patient
(Al-Quds University, 2023-03-11) maram mohammad motee ghazawna; مرام محمد مطيع غزاونة
Magnetic resonance imaging (MRI) is a medical tool that can provide detailed information about the inner structure of a person's body. The use of the fluid-attenuated inversion recovery (FLAIR) sequence in imaging the brain is very useful, as it can help identify subtle changes in the brain's structure and function. Due to the sensitivity of MRI to artifacts, it is not always possible to achieve high-quality imaging. The presence of motion artifacts can affect the overall diagnostic value. In this study dipole filling for k-space (BLADE) was implemented for 46 different images with different motion types including right rotation, left rotation, right bending, left bending, flexion, extension, and combination. In this work, we aimed to measure signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and percentage of signal ghosting (PSG). RADIANT DICOM viewer was used to calculate signal intensity (SI) and its standard deviation (SD), the SD is used as the noise index. ImageQC was used to calculate PSG while these measurements are plotted in Microsoft Excel. In this research, we used a control group of 46 patients who have standard images which use the cartesian filling for k-space for comparing the measurements with standard FLAIR sequence. Results showed using BLADE lead to a significant improvement in SNR, CNR, and ghosting in almost all types of motion while failing to correct ghosting from severe patient motion. The mean value of SNR was 1.08 for the dipole filling (BLADE) sequence and significantly reduced to 0.92 for the routine sequence (p<0.05). While the mean CNR was 0.75 for dipole filling and significantly reduced to 0.49 for routine sequence (p<0.05). Finally, the mean PSG for dipole filling was 0.75 and significantly reduced to 0.18 for routine sequence (p<0.05). In conclusion, the dipole filling sequence enhances SNR, and CNR due to flow and eye motion. Although BLADE reduced ghosting artifacts in most types of motion, BLADE was unable to eliminate ghosting appearance from the severe patient motion.
Evaluation of antibiotics resistance including fosfomycin in Pseudomonas aeruginosa isolates from cystic fibrosis patients in Palestinian Hospital over 5 years
(Al-Quds University, 2021-06-07) Bayan Asad “Mohammad Rajab” Subb Laban; بيان أسعد محمد رجب صب لبن
Background: Antipseudomonal agents, like other antibiotics, will develop a resistance when taken continuously for many years. In diseases like cystic fibrosis (CF),the most dangerous pathogen colonizing the lungs is Pseudomonas aeruginosa and antibiotic resistance has a high chance to occur. In Palestine, there is no accurate data about resistance in these bacteria among CF patients. The increased prevalence of multi-drug resistant strains, allergic reactions, nephrotoxicity and other side effects of antibiotic used among patients with CF limits the number of antibiotics available to treat pulmonary exacerbations. Fosfomycin, a unique broad spectrum bactericidal antibiotic, might offer an alternative therapeutic option in such cases. Objectives: The aim of this study was to determine the level and change in the rates of resistance over the years for mostly commonly used antibiotics in Pseudomonal infection in CF patients. In addition, the study evaluated the effect of fosfomycin on this bacteria. Methods: To study antibiotics resistance tested in sputum samples over the past 5 years, a retrospective study was carried out in the Department of Microbiology at Caritas Baby Hospital. Clinical and microbiological data were extracted from medical database for pediatric CF patients. The results were analyzed using Microsoft Excel Software 2010 and Statistical Package for Social Sciences (SPSS) program version 20. In addition, 129Pseudomonas aeruginosa sputum samples from CF patients were tested for fosfomycin sensitivity by using two different methods minimum inhibitor concentration (MIC) and disc diffusion(DD). Results: The sensitivity to commonly used antibiotics in treatment P.aeruginosa infection in CF pediatric patients in Palestine was92.3%, 91.9%, 89.1%, 87.7%, 76.5% and 73.5% for ciprofloxacin, ceftazidime, piperacillin-tazobactam, meropenem, amikacin and gentamicin; respectively. Over the past 5 years, the sensitivity was oscillating slightly with no deterioration in sensitivity toward these antibiotics. The vast majority of patients are from the south of the west bank (70.1%), and also the resistance in this area is higher for all antibiotics. Males are slightly more sensitive than females. Regarding ages, as the age increased, resistance to antibiotics increased. In vitro, due to the lack of susceptibility breakpoint of fosfomycin for P.aeruginosa in CLSI and EUCAST, sensitivity to fosfomycin according to MIC results was determined based on the existing CLSI breakpoints for the Enterobacteriaceae; ≤64 is sensitive. MIC method showed good activity for fosfomycin toward P.aeruginosa isolates from CF patients; nearly 40% sensitive, the most sensitivity was in mucoid type (57.5%). DD method showed a strong correlation with MIC method, Pearson Correlation between MIC and DD 200 μg was -0.889, between MIC and DD 50 μg was -0.768, and also 0.932 between DD 200μg and DD 50μg. Conclusions: In Palestine, the sensitivity to commonly used antibiotics in treatment P.aeruginosa infection in CF pediatric patients was stable, and there was no deterioration in sensitivity toward these antibiotics over the past 5 years. Fosfomycin showed a good sensitivity towards Palestinian P.aeruginosa isolates in CF patients, so it can be considered as a choice in the antibiotics used in treating P.aeruginosa infection (particularly the mucoid type) in CF patients in the future, but it still needs more research. Keywords: Cystic Fibrosis, Pseudomonas Aeruginosa , Fosfomycin, Bacterial Resistance.

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