Perception and Willingness to Use Telepharmacy Among the General Population in Jordan.

Objective: This research aimed to explore how telepharmacy is perceived, whether it would be willingly used by the overall population in Jordan, and the associated socioeconomic disparities that might affect its acceptance. Methods: This is a survey-based cross-sectional study involving the general public of Jordan. The study took place in various Jordanian cities from May 2nd to June 1st, 2023. Using Google forms, the questionnaire was shared through various social media channels (such as Facebook and WhatsApp). Results: The questionnaire received responses from 800 participants. The data showed that a sizable portion of the Jordanian population were unaware of telepharmacy (n= 343, 42.9%), and a majority had never utilized it (n= 131, 16.4%). The participants viewed the main advantage of telepharmacy as minimizing unnecessary trips to pharmacies (n= 668, 83.5%) and reducing travel time and expenses (n= 632, 79.0%). However, the primary concern was the mental effort required to use this service (n= 465, 58.1%). Of the respondents, 61.3% (n= 490) indicated a willingness to adopt telepharmacy services in the future. Regression analysis indicated that men were more likely to use this service compared to women (OR= 1.947, p<0.001), and people living in northern and southern Jordan exhibited a greater willingness compared to those inhabiting the central region (OR= 2.168, p<0.001). Conclusion: The results reveal a positive attitude towards and a significant readiness to embrace telepharmacy among the Jordanian population. However, for broader acceptance and utilization, apprehensions regarding the service need to be addressed. Doing so could improve access to pharmaceutical care, particularly for patients living in far-flung areas of Jordan.

Video-based teach-to-goal intervention on inhaler technique on adults with asthma and COPD: A randomized controlled trial.

BACKGROUND: Incorrect use of inhalers is a problem associated with poor patient outcomes. Despite improvement in the technique after verbal educations, this deteriorates over-time requiring re-enforcement through different educative strategies. This study aimed to assess the impact of a novel video-based teach-to-goal (TTG) educational intervention on: mastery of inhaler technique, disease control, medication adherence and disease-related quality of life (QoL) over-time among asthma and COPD patients. METHODS: This prospective, open-label, randomized controlled trial was registered in ClinicalTrials.gov: Identifier NCT05664347. After baseline assessment participants received either a verbal (control group) or a video-based (intervention group) TTG strategy. After 3-month the intervention was assessed for impact on the intended outcomes. Inhaler technique was assessed using standardized checklists, disease control using the Asthma control test and COPD assessment test respectively for asthma and COPD patients while adherence using the Morisky Green Levine scale. For QoL, the mini asthma quality of life questionnaire and the St. George respiratory questionnaire were used for asthmatic and COPD patients, respectively. Differences in outcomes between intervention-control groups were analyzed using either Chi-Square (X2)/Fisher Exact or Mann Whitney test. The impact of intervention on outcomes over-time was examined using either McNemar or Wilcoxon test. RESULTS: At baseline, intervention (n = 51) and control (n = 52) groups had comparable demographic/clinical characteristics. At follow-up, inhaler technique improved among intervention group compared to control group (93.4% vs 67%) and to baseline (93.4% to 49.5%), (P<0.05). Similarly, medication adherence ameliorated among the intervention group in comparison to control group (88.2% to 61.5%) and to baseline (88.2% to 66.7%), (P<0.05). In regards to disease control, results showed an amelioration among the intervention group compared to baseline (35.3% to 54.9%) (P<0.05). QoL scores improved significantly among asthma patients (intervention group) at follow-up vs baseline. Better scores were also observed for COPD patients compared to controls, (P<0.05). CONCLUSION: Video-based (TTG) was effective in enhancing inhaler technique over time as well as improving disease control, medication adherence, and QoL. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05664347. https://clinicaltrials.gov/ct2/show/NCT05664347.

Validation of the Arabic Version of the Health Literacy (HLS-Q12) Questionnaire in chronically ill patients.

Health literacy (HL) is an essential component of public health. Few tools are used to measure HL in Arabic-speaking countries, essentially the Short Test of Functional Health Literacy in Adults and the Single Item Literacy Screener. The new 12-item version of the European Health Literacy Survey Questionnaire (HLS-Q12), has not been validated in the Arabic language. This study aimed to translate the English version of HLS-Q12 into Arabic, test its structure and explain any variance in HLS-Q12 scores, allowing its use in Arabic-speaking healthcare contexts. A forward-backward translation was adopted. Reliability was assessed using Cronbach's α. Confirmatory factor analysis (CFA) and Rasch Model evaluated the model fit of the Arabic version of HLS-12. The effects of different patient-related variables on HLS-Q12 scores were tested using linear regression. A total of 389 patients visiting the site hospital outpatient clinics participated in the study. HLS-Q12 mean ± SD score was 35.8 ± 5.0, 50.9% of the participants showed an intermediate HL score. Good reliability (α = 0.832) was observed. CFA confirmed the scale unidimensionality. Rasch analysis indicated HLS-Q12 items to be within the fit acceptable thresholds except for Item 12. The only item that displayed unordered response categories was Item 4. Most of the items were considered relatively easy by respondents. Linear regression revealed age, education, healthcare-related education and income to have effects significantly different from zero on HLS-Q12 score. Interventions targeting the most health-disparate groups of individuals with characteristics contributing to lower HL, are needed.

Translation and validation of the Arabic version of the Morisky, Green and Levine (MGL) adherence scale.

The Morisky Green Levine (MGL) adherence scale is a 4-item tool used for the detection of medication nonadherence among patients with chronic health conditions. Despite being widely used in Arabic-speaking research contexts, it has never been validated in Arabic language. The aim of this study was to translate and validate the MGL tool into Arabic. A standard forward-backward process was used to translate the questionnaire. Cronbach's alpha coefficient was measured to assess internal consistency of the scale. The test-retest reliability measured the consistency of participants' responses over time. Construct validity was evaluated by Explanatory factor analysis (EFA); Kaiser-Meyer-Olkin value and Bartlett's test of sphericity were determined. Convergent validity was assessed using a preexisting medications Arabic Adherence Assessment Tool (AAAT). The model fit was evaluated using confirmatory factor analysis (CFA). Associations between the MGL scale scores and the patient demographic/clinical characteristics were tested by linear regressions. A total of 201 participants were included into the study. The MGL scale categorization revealed that 20.9%, 59.2% and 19.9% of the participants had high, moderate and low levels of adherence respectively. Adequate internal consistency (alpha = 0.593) was observed. A significant strong ICC and Pearson's correlations were generated between responses at time 1 and time 2. EFA results elucidated the suitability of the data for factor analysis. Pearson's coefficient (r) revealed a significant strong correlation between MGL scale and AAAT. CFA results confirmed a good fit for the suggested model. Linear regression revealed higher number of medications, more frequent outpatient clinic visits and not experiencing medication adverse effect factors significantly associated with better adherence. The Arabic version of MLG scale is a reliable valid tool to assess adherence among Arabic-speaking communities. Implementing interventions targeting patients not compliant to regular clinic visits and those at higher risk of experiencing medication side effects can greatly enhance medication adherence.

Correlation of skin cancer and actinic keratosis-related knowledge and sun protection behaviors and sunscreen use among a sample of Jordanian population.

BACKGROUND: The incidence of skin cancer and actinic keratosis has increased worldwide. Measuring the public awareness, attitude, and knowledge about these diseases and the skin protection behaviors are highly important to undertake preventive measures. METHODS: To investigate skin cancer and actinic keratosis-related knowledge, sun protection behaviors, and sunscreen usage among Jordanians, a questionnaire was developed. The questionnaire was provided as a google form to individuals via social media and the data were analyzed using SPSS® 23. RESULTS: A total of 1277 individuals, aged 18-65 years filled the questionnaire. The median melanoma and actinic keratosis knowledge score were 7 (4-9) and 4 (0-9), respectively. The melanoma knowledge was higher among females, those with a medical background, a high level of education, and in the central region, whereas the AK knowledge was higher among those with a medical background. Overall, 75.9% of the participants used sunscreen at least often to prevent sunburn, uneven skin tone, or tanning, 72% were using sunscreen with an SPF of 30 at least. However, 45.3% and 49.2% of sunscreen users did not comply with application, and reapplication times, respectively. Moreover, 58.4% of participants applied less than the recommended amount of sunscreen. CONCLUSION: Our study revealed that public awareness of actinic keratosis is low among Jordanians. Although it was found that a high proportion of Jordanians use sunscreens there are deficits in sunscreen practice indicating an urgent need to design effective interventions to increase awareness of actinic keratosis and correct use of sunscreen via health campaigns or healthcare professions.

Prevalence and predictors of non-adherence to short-term antibiotics: A population-based survey.

Non-adherence to antibiotics is a well-known, core player to antibiotic resistance. The current adherence behavior toward short-term antibiotic regimens has never been investigated before in Jordan. This study assessed the prevalence and predictors of non-adherence to short-term antibiotics among Jordanians and investigated participants' views about different reasons related to antibiotics non-adherence. A cross-sectional face-to-face survey-based interview was conducted in three hospital pharmacies in Jordan. Adults and mother of children (≤12 years old) who completed their short course treatment (<30 day) of oral antibiotic within the last month were recruited. A total of 2000 participants (adults: 1000 and mothers of children: 1000) were included in the study with a response rate of 91.60%. The prevalence of non-adherence was estimated to be 32.10%. Non-adherent respondents scored a lower Medication Adherence Report Scale [16.76±5.02 vs. 23.04 ±3.24] than adherent respondents (p<0.001). Adults without comorbidity and children with higher number of doses per regimen were significantly less adherent to antibiotic [(OR = 0.615, 95%CI = 0.444-0.853, p = 0.004) and (OR = 0.965, 95%CI = 0.950-0.981, p<0.001)], respectively. Patients-related factors were the most common antibiotic non-adherence reason reported by the participants. The multivariate analysis for all the participants (adults and children), indicated that mothers were 2.6 times more likely to be adherent in giving antibiotics to their children than adults (p<0.001). These findings highlight that more than half of the participants were adherent to short-term antibiotics. However, improving the current prescription-related practices and implementing pharmaceutical consultation services upon antibiotic dispensing are encouraged.

Clinical trials: Predictors of knowledge and attitudes towards participation.

AIMS: Clinical trials (CTs) are critical to advancing of patient care. Understanding the public's knowledge and the attitudes towards participating in CTs is important for their successful implication. In Jordan this data are currently not available. The present study aimed to explore the knowledge, attitude and perception of Jordanians towards CTs participation. METHODS: A cross-sectional study was conducted on 1216 Jordanians recruited from public hospitals and pharmaceutical research centres. RESULTS: About 20.5% of the respondents have previously participated in a CT. About 68.3% and 50.1% had good knowledge and positive attitude towards CTs, respectively. Good knowledge was associated with male gender (OR = 1.696, 95% CI = 1.284-0.240, P < .001), higher education (OR = 1.433, 95% CI = 1.107-1.856, P = .006) and healthy condition (OR = 1.822, 95% CI = 1.234-2.690, P = .003); while older age was associated with a poor knowledge (OR = 0.985, 95% CI = 0.972-0.998, P = .026). Female gender (OR = 1.817, 95% CI = 1.406-2.349, P < .001), higher education (OR = 1.294, 95% CI = 1.017-1.646, P = .036) and previous participation (OR = 1.919, 95% CI = 1.388-2.653, P < .001) were factors predicting the positive attitudes. A very weak positive correlation was found between knowledge and attitude (Spearman's r = 0.074, P = .01). Regarding perceptions, most of the respondents (85.3%) perceive that CTs are conducted in an ethical manner in Jordan, only 52.9% however feel comfortable towards participation. A moderate positive correlation was found between knowledge and perception (Spearman's r = 0.275, P < .001). Taking part in a CT significantly affect knowledge, attitudes and perceptions. CONCLUSIONS: This study revealed important insights regarding knowledge, attitudes and perception of Jordanians towards CTs. Educational interventions can improve awareness of the ethical standards under which CTs are conducted affecting the perception to participate. Promotion of CTs among patients and healthy individuals is needed to increase participation.

Attitudes of pharmacy students towards patient safety: a cross-sectional study from six developing countries.

OBJECTIVE: To evaluate the attitudes of undergraduate pharmacy students towards patient safety in six developing countries. DESIGN: A cross-sectional study. SETTING: Participants were enrolled from the participating universities in six countries. PARTICIPANTS: Undergraduate pharmacy students from the participating universities in six developing countries (Jordan, Saudi Arabia, Kuwait, Qatar, India and Indonesia) were invited to participate in the study between October 2018 and September 2019. PRIMARY OUTCOME: Attitudes towards patient safety was measured using 14-item questionnaire that contained five subscales: being quality-improvement focused, internalising errors regardless of harm, value of contextual learning, acceptability of questioning more senior healthcare professionals' behaviour and attitude towards open disclosure. Multiple-linear regression analysis was used to identify predictors of positive attitudes towards patient safety. RESULTS: A total of 2595 students participated in this study (1044 from Jordan, 514 from Saudi Arabia, 134 from Kuwait, 61 from Qatar, 416 from India and 429 from Indonesia). Overall, the pharmacy students reported a positive attitude towards patient safety with a mean score of 37.4 (SD=7.0) out of 56 (66.8%). The 'being quality-improvement focused' subscale had the highest score, 75.6%. The subscale with the lowest score was 'internalising errors regardless of harm', 49.2%. Female students had significantly better attitudes towards patient safety scores compared with male students (p=0.001). Being at a higher level of study and involvement in or witnessing harm to patients while practising were important predictors of negative attitudes towards patient safety (p<0.001). CONCLUSION: Patient safety content should be covered comprehensively in pharmacy curricula and reinforced in each year of study. This should be more focused on students in their final year of study and who have started their training. This will ensure that the next generation of pharmacists are equipped with the requisite knowledge, core competencies and attitudes to ensure optimal patient safety when they practice.

Metformin Improves the Depression Symptoms of Women with Polycystic Ovary Syndrome in a Lifestyle Modification Program.

BACKGROUND: Metformin is commonly prescribed to manage polycystic ovary syndrome (PCOS), which is one of the most common endocrine disorders among women of childbearing age and is associated with high prevalence rates of depression and anxiety. OBJECTIVE: This study's objective was to determine the impact of prescribed metformin on depression and anxiety levels of patients with PCOS. METHODS: This prospective, multi-center, cohort study examined the impact of prescribed metformin on the depression and anxiety of women with PCOS in four gynecology clinics in Saudi Arabia and Jordan. The women had recently been prescribed metformin along with lifestyle modifications, such as diet and exercise, and were compared to another group of women with PCOS who were prescribed lifestyle modifications only. Depression and anxiety were assessed at baseline and three months later using the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder (GAD-7) scale, respectively. Health-related quality of life was measured using the Short Form Health Survey (SF-36). Multiple logistic regression analyses were conducted to examine the impact of metformin on depression and anxiety. RESULTS: Eighty-six women participated in the study: 53 were prescribed metformin with lifestyle modifications, and 33 were prescribed lifestyle modifications only. The women on metformin had 70% lower odds of having major depression (PHQ-9≥10) (OR=0.302, P=0.045); however, no significant effect of metformin on anxiety (GAD-7≥10) was found. CONCLUSION: Metformin may have a role in the management of depression symptoms among patients with PCOS; however, its potential antidepressant effect should be further examined in randomized double-blind placebo-controlled clinical trials.

The anti-cancer effects of phenformin in thyroid cancer cell lines and in normal thyrocytes.

Phenformin is a biguanide drug which, besides the original anti-diabetic effect, also exerts anti-cancer effects. The aim of this study was to further characterize these latter in terms of both cell-viability and modulation of the secretion of the pro-tumorigenic chemokine CXCL8. Normal human thyrocytes in primary cultures (NHT) and thyroid cancer cell lines, TPC-1 and 8505C (RET/PTC and BRAFV600E mutated, respectively) were treated with increasing concentrations of phenformin at different times. Cell-viability was assessed by WST-1 and further characterized by AnnexinV/PI staining and cell proliferation colony-assay. CXCL8 levels were measured in cell supernatants. Phenformin reduced cell-viability in TPC-1 and 8505C and their ability to form colonies. In NHT cells, phenformin affected cell-viability only at the maximal dose but interestingly it inhibited CXCL8 secretion at all the concentrations not affecting cell-viability. Phenformin had no effect on CXCL8 secretion in thyroid cancer cell lines. Thus, phenformin exerts anti-cancer effects on both cancer cells (cell death induction) and surrounding normal cells (inhibition of CXCL8 secretion). These results highlight that the anti-cancer effects of phenformin are multifaceted and effective on both solid and soluble components of the tumor-microenvironment.

Chemodiversity and Antiproliferative Activity of the Essential Oil of Schinus molle Growing in Jordan.

The leaves and unripe and fully-grown fruits of Schinus molle were collected from three geographical regions of Jordan: Amman (the Mediterranean), Madaba (Irano-Turanean), and Sahab (Saharo-Arabian). The hydrodistilled volatile oils of fresh and dried leaves and fruits were analyzed by gas chromatography-mass spectrometry (GC/MS). The actual composition of the emitted volatiles was determined using Solid Phase Micro-Extraction (SPME). α- and ß-Phellandrenes were the major components in all the analyzed samples. Quantitative differences were observed in the obtained essential oils (0.62-5.25 %). Additionally, cluster analysis was performed. Biologically, the antiproliferative activity of the essential oil, ethanol, and water extracts of the fruits and leaves was screened on Caco2, HCT116, MCF7, and T47D cell lines. The essential oil and ethanol extracts exhibited a dose-dependent inhibition of cell growth with IC50 ranging between 21 and 65 µg/mL. The water extract did not exhibit any antiproliferative activity against the investigated cell lines.

The BRAF-inhibitor PLX4720 inhibits CXCL8 secretion in BRAFV600E mutated and normal thyroid cells: a further anti-cancer effect of BRAF-inhibitors.

CXCL8 is a chemokine secreted by normal and thyroid cancer cells with proven tumor-promoting effects. The presence of BRAFV600E mutation is associated with a more aggressive clinical behavior and increased ability to secrete CXCL8 by papillary-thyroid-cancer cells. Aim of this study was to test the effect of the BRAF-inhibitor (PLX4720) on the basal and TNF-α-induced CXCL8 secretions in BRAFV600E mutated (BCPAP, 8305C, 8505C), in RET/PTC rearranged (TPC-1) thyroid-cancer-cell-lines and in normal-human-thyrocytes (NHT). Cells were incubated with increasing concentrations of PLX4720 alone or in combination with TNF-α for 24-hours. CXCL8 concentrations were measured in the cell supernatants. PLX4720 dose-dependently inhibited the basal and the TNF-α-induced CXCL8 secretions in BCPAP (F: 14.3, p < 0.0001 for basal and F: 12.29 p < 0.0001 for TNF-α), 8305C (F: 407.9 p < 0.0001 for basal and F: 5.76 p < 0.0001 for TNF-α) and 8505C (F:55.24 p < 0.0001 for basal and F: 42.85 p < 0.0001 for TNF-α). No effect was found in TPC-1 (F: 1.8, p = 0.134 for basal; F: 1.6, p = 0.178 for TNF-α). In NHT an inhibitory effect was found only at the highest concentration of PLX4720 (F: 13.13 p < 0.001 for basal and F: 2.5 p < 0.01 for TNF-α). Cell migration assays showed that PLX4720 reduced both basal and CXCL8-induced cell migration in BCPAP, 8305C, 8505C and NHT but not in TPC-1 cells. These results constitutes the first demonstration that PLX4720 is able to inhibit the secretion of CXCL8 in BRAFV600E mutated thyroid cancer cells indicating that, at least some, of the anti-tumor activities of PLX4720 could be exerted through a lowering of CXCL8 in the thyroid-cancer-microenvironment.

Impact of a pharmacist-provided information booklet on knowledge and attitudes towards oral contraception among Jordanian women: an interventional study.

OBJECTIVES: Jordan has high rate of unintended pregnancy, which is largely attributed to limited knowledge and misconceptions about contraceptive methods, namely oral contraceptive pills (OCPs). The aim of this study was to examine the effect of a pharmacist-provided information booklet on increasing the knowledge of Jordanian women about safe and effective OCP use. METHODS: This was a randomised interventional study. One hundred and sixty women who had used OCPs at least once in their lifetime were randomised to receive conventional counselling (control group) or a pharmacist-provided booklet (intervention group). Knowledge about and attitude towards OCP use were assessed before and immediately after the intervention, and at three-month follow-up. RESULTS: The mean knowledge score (out of 5) of women in the intervention group improved significantly from 1.76 at baseline (standard deviation [SD] 1.25) to 5.00 (p < .000) directly after the intervention, which then slightly decreased to 4.93 (SD 0.31; p = .033) at follow-up. The baseline mean knowledge score of the control group was 1.29 (SD 1.12) and did not significantly increase over time. It was also considerably lower than that of the intervention group both immediately after the intervention and at follow-up. As regards mean attitude score (out of 6), the control group demonstrated no changes from baseline, whereas the intervention group improved significantly from 5.15 (SD 1.63) to 5.50 (SD 1.36; p = .014). CONCLUSIONS: Provision of an information booklet by pharmacists to women in Jordan using OCPs is highly recommended. Studies with a larger sample size and from different regions of Jordan are recommended.

Effect of Interferon-γ on the Basal and the TNFα-Stimulated Secretion of CXCL8 in Thyroid Cancer Cell Lines Bearing Either the RET/PTC Rearrangement Or the BRAF V600e Mutation.

CXCL8 displays several tumor-promoting effects. Targeting and/or lowering CXCL8 concentrations within the tumor microenvironment would produce a therapeutic benefit. Aim of this study was to test the effect of IFNγ on the basal and TNFα-stimulated secretion of CXCL8 in TCP-1 and BCPAP thyroid cancer cell lines (harboring RET/PTC rearrangement and BRAF V600e mutation, resp.). Cells were incubated with IFNγ (1, 10, 100, and 1000 U/mL) alone or in combination with TNF-α (10 ng/mL) for 24 hours. CXCL8 and CXCL10 concentrations were measured in the cell supernatants. IFNγ inhibited in a dose-dependent and significant manner both the basal (ANOVA F: 22.759; p < 0.00001) and the TNFα-stimulated (ANOVA F: 15.309; p < 0.00001) CXCL8 secretions in BCPAP but not in TPC-1 cells (NS). On the other hand, IFNγ and IFNγ + TNF-α induced a significant secretion of CXCL10 in both BCPAP (p < 0.05) and TPC-1 (p < 0.05) cells. Transwell migration assay showed that (i) CXCL8 increased cell migration in both TPC-1 and BCPAP cells; (ii) IFNγ significantly reduced the migration only of BCPAP cells; and (iii) CXCL8 reverted the effect of IFNγ. These results constitute the first demonstration that IFNγ inhibits CXCL8 secretion and in turn the migration of a BRAF V600e mutated thyroid cell line.

The influence of patients' knowledge on adherence to their chronic medications: a cross-sectional study in Jordan.

BACKGROUND: Non-adherence to long-term therapy for chronic illnesses is considered the major reason why patients fail to reach their clinical goals, resulting in suboptimal health outcomes, death, and extra costs on the health care systems. Knowledge about the disease and prescription medications, an understanding of the reason the medication is needed, and good expectations or attitudes toward treatment, all contribute to a better medication-taking behavior and are associated with higher rates of adherence. OBJECTIVE: This study examines the relationship between knowledge and adherence of patients receiving long-term therapy for one or more chronic illnesses in Jordan. SETTINGS: The study was conducted in the out-patient clinics of two Jordanian hospitals (The University of Jordan Hospital and Jordan Hospital). METHODS: This was a cross-sectional study that included 902 patients. The correlation between patients' knowledge about their chronic medications and adherence was assessed. Effects of several sociodemographic characteristics were investigated in regard to knowledge and adherence. MAIN OUTCOME MEASURES: Knowledge was assessed by a modified version of the McPherson index, and the Morisky Medication Adherence Scale was used to assess medication adherence. RESULTS: A significant correlation was found between patients' knowledge and their adherence to medications (r = 0.357, p < 0.001). Most of the participants had low adherence. Younger age, higher education levels, high income, fewer medications and diseases were significant predictors of higher knowledge levels. Knowledgeable patients were found to be twice as likely to have moderate-to-high adherence as their unknowledgeable counterparts. Similarly, high income and higher education were associated with higher adherence scores. CONCLUSION: Forgetfulness and aversion toward medications were the most common barriers to medication adherence. This implicates that clinicians and health care policy makers should direct their effort toward two main strategies to improve adherence increasing awareness and education of effective ways to remind patients about their medications.

Nonsteroidal anti-inflammatory drug-activated gene-1 plays a role in the impairing effects of cyclooxygenase inhibitors on gastric ulcer healing.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can impair gastric ulcer healing. This study investigates the involvement of NSAID-activated gene-1 (NAG-1) in ulcer repair impairment by cyclooxygenase (COX) inhibitors. Gastric ulcers were induced in rats by acetic acid. Four days later, animals received daily intragastric indomethacin (nonselective COX-1/COX-2 inhibitor; 1 mg/kg), 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (selective COX-1 inhibitor; 2.5 mg/kg), (5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl) phenyl-2(5H)-furanone (DFU) (selective COX-2 inhibitor; 5 mg/kg), celecoxib (selective COX-2 inhibitor; 1 mg/kg), and valdecoxib (selective COX-2 inhibitor; 1 mg/kg), for 1, 3, or 7 days. Ulcerated tissues were processed to assess: 1) COX-1, COX-2, NAG-1, proliferating cell nuclear antigen (PCNA), and activated caspase-3 expression; 2) ulcer area; and 3) prostaglandin E(2) (PGE(2)) levels. COX-1 expression in ulcerated tissues was decreased, whereas COX-2 expression was enhanced. Ulcer healing was delayed by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. Ulcer PGE(2) levels were decreased by SC-560, DFU, celecoxib, valdecoxib, and indomethacin. NAG-1 was overexpressed in ulcerated tissues and further enhanced by indomethacin, DFU, and SC-560, but not by celecoxib or valdecoxib. PCNA expression in ulcerated areas was reduced by indomethacin, but not by the other test drugs. The expression of activated caspase-3 in ulcers was increased and enhanced further by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. These findings indicate that: 1) COX inhibitors exert differential impairing effects on gastric ulcer healing, through mechanisms unrelated to the inhibition of COX isoforms and prostaglandin production; and 2) NAG-1 induction, followed by activation of proapoptotic pathways, can contribute to the impairing effects of COX inhibitors on ulcer healing.

Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders.

The adenosine pathway is a powerful evolutionarily selected mechanism aimed at a fine modulation of inflammatory responses and protection of tissues from injuries. Adenosine exerts its modulatory effects via interaction with G protein-coupled receptors, designated as A(1), A(2A), A(2B) and A(3). In this regard, extracellular adenosine concentrations are critical in determining its ability of regulating several biological functions. The levels achieved by adenosine in close proximity of its receptors are strictly regulated by a variety of dynamic mechanisms, including intracellular and extracellular biosynthesis, transport and metabolism, based on tissue energy status. In this context, the catabolic enzyme adenosine deaminase (ADA) represents a critical checkpoint in the regulation of extracellular adenosine levels and, consequently, in the control of receptor stimulation, thus playing a pivotal role in the modulation of purinergic responses to several pathophysiological events, such as chronic pulmonary diseases, rheumatoid arthritis, inflammatory bowel diseases and sepsis. This article reviews current data on the role played by ADA in the regulation of immune system activity through its modulation of adenosine pathways. Particular attention has been paid to the involvement of ADA in the pathophysiology of relevant inflammatory diseases. In addition, the interest in designing and developing novel ADA inhibitors, as new tools potentially useful for the therapeutic management of inflammatory disorders, has been discussed.

Effects of esomeprazole on healing of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers in the presence of a continued NSAID treatment: Characterization of molecular mechanisms.

Proton pump inhibitors promote ulcer repair in nonsteroidal anti-inflammatory drug (NSAID)-treated patients with ongoing NSAID-induced gastric toxicity, although the underlying mechanisms remain unclear. We examined the healing mechanisms of esomeprazole on NSAID-induced gastric ulcerations in the presence of a continued NSAID treatment. Ulcerations were induced in rats by oral indomethacin (6µmol/kg/day) for 14 days. Indomethacin administration was continued, alone or combined with equivalent acid inhibitory doses of esomeprazole (5µmol/kg/day), lansoprazole (15µmol/kg/day) or famotidine (20µmol/kg/day), for additional 7 days. Stomachs were then processed for: histomorphometric analysis of mucosal injury; mucosal levels of prostaglandin E(2) (PGE(2)) and malondialdehyde (MDA); expression of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA), caspase-3, and cyclooxygenase-2 (COX-2) (Western blot); expression of Ki-67 (immunohistochemistry). Indomethacin for 14 days elicited mucosal damage, reduced PGE(2) levels and increased MDA. After additional 7 days, indomethacin induced the following effects: further enhancement of mucosal damage and MDA content; decrease in PGE(2) levels; increase in COX-2 and activated caspase-3 expression; decrease in VEGF, PCNA and Ki-67 expression. In the presence of indomethacin, esomeprazole and lansoprazole were more effective than famotidine in promoting resolution of mucosal damage. Concomitantly, esomeprazole and lansoprazole, but not famotidine, restored PCNA and Ki-67 expression, and normalized MDA levels. Moreover, esomeprazole, lansoprazole and famotidine partly counteracted caspase-3 activation, without affecting VEGF expression. The healing activity of esomeprazole on indomethacin-induced gastric ulcerations can be ascribed to two mechanisms: (1) acid-dependent reduction of pro-apoptotic signalling; (2) acid-independent restoration of proliferating/repairing pathways.

Differential recruitment of high affinity A1 and A2A adenosine receptors in the control of colonic neuromuscular function in experimental colitis.

This study investigated the expression of A(1) and A(2A) receptors in the rat colonic neuromuscular compartment, and characterized their roles in the control of motility during inflammation. Colitis was induced by 2,4-dinitrobenzenesulfonic acid. A(1), A(2A) receptors, and ecto-5'-nucleotidase (CD73, adenosine producing enzyme) mRNA expression was examined by RT-PCR. The effects of DPCPX (A(1) receptor antagonist), CCPA (A(1) receptor agonist), 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (A(2A) receptor antagonist), 4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride (A(2A) receptor agonist), AOPCP (CD73 inhibitor) were tested on electrically or carbachol-evoked contractions in colonic longitudinal muscle preparations. In normal colon, RT-PCR revealed the presence of A(1) receptors, A(2A) receptors and CD73, and an increased expression of A(2A) receptors and CD73 was detected in inflamed tissues. In normal colon, DPCPX or 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol enhanced electrically-induced contractions, while in inflamed preparations the effect of DPCPX no longer occurred. In normal colon, CCPA or 4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl] benzenepropanoic acid hydrochloride decreased electrically-induced contractions. Under inflammation, 4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl] benzenepropanoic acid hydrochloride reduced electrically evoked contractions with higher efficacy, while the inhibition by CCPA remained unchanged. A(1) and A(2A) receptor ligands did not affect carbachol-induced contractions. AOPCP enhanced electrically-induced contractions and prevented the contractile effects of 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol, without interfering with DPCPX, both in normal and inflamed colons. These results indicate that, in normal colon, both A(1) and A(2A) receptors contribute to the inhibitory control of motor functions at neuronal level. Under bowel inflammation, A(1) receptor loses its modulating actions, while the recruitment of A(2A) receptor by CD73-dependent endogenous adenosine drives an enhanced inhibitory control of colonic neuromotility.

The blockade of adenosine deaminase ameliorates chronic experimental colitis through the recruitment of adenosine A2A and A3 receptors.

Adenosine modulates immune/inflammatory reactions. This study investigates the expression of adenosine deaminase in the inflamed colon, the effects of adenosine deaminase inhibitors on established colitis, and the recruitment of adenosine receptors by endogenous adenosine after adenosine deaminase blockade. Adenosine deaminase expression was determined by Western blot. The effects of 4-amino-2-(2-hydroxy-1-decyl)pyrazole[3,4-d]pyrimidine (APP; a novel adenosine deaminase inhibitor), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; a reference adenosine deaminase inhibitor), dexamethasone, and selective adenosine receptor antagonists were tested in rats with 2,4-dinitrobenzenesulfonic acid-induced colitis. Systemic (food intake, body and spleen weight) and colonic [macroscopic/microscopic damage, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and malondialdehyde (MDA)] inflammatory parameters were assessed. Test drugs were administered intraperitoneally for 6 days, starting at day 5 from colitis induction. Adenosine deaminase was detected in normal colon, and its expression was increased in inflamed tissues. Colitis was associated with decreased food intake and body weight, augmented spleen weight, and increased levels of colonic TNF-α, IL-6, and MDA. APP or EHNA, but not dexamethasone, improved food intake and body weight. APP, EHNA, and dexamethasone counteracted the increments of spleen weight, ameliorated macroscopic and microscopic indexes of inflammation, and reduced TNF-α, IL-6, and MDA levels. The beneficial effects of APP and EHNA on inflammatory parameters were prevented by the pharmacological blockade of A(2A) or A(3) receptors, but not A(1) or A(2B). The present results show that: 1) bowel inflammation is associated with an enhanced adenosine deaminase expression; and 2) the anti-inflammatory actions of adenosine deaminase inhibitors against chronic established colitis depend on the sparing of endogenous adenosine, leading to enhanced A(2A) and A(3) receptor activation.