Urolithin A's Antioxidative, Anti-Inflammatory, and Antiapoptotic Activities Mitigate Doxorubicin-Induced Liver Injury in Wistar Rats.

Human colon microbiota produce a metabolite called urolithin A (URO A) from ellagic acid and linked compounds, and this metabolite has been demonstrated to have antioxidant, anti-inflammatory, and antiapoptotic activities. The current work examines the various mechanisms through which URO A protects against doxorubicin (DOX)-induced liver injury in Wistar rats. In this experiment, Wistar rats were administered DOX intraperitoneally (20 mg kg-1) on day 7 while given URO A intraperitoneally (2.5 or 5 mg kg-1 d-1) for 14 days. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyl transferase (GGT) were measured. Hematoxylin and eosin (HE) staining was used to evaluate histopathological characteristics, and then antioxidant and anti-inflammatory properties were evaluated in tissue and serum, respectively. We also looked at how active caspase 3 and cytochrome c oxidase were in the liver. The findings demonstrated that supplementary URO A therapy clearly mitigated DOX-induced liver damage. The antioxidant enzymes SOD and CAT were elevated in the liver, and the levels of inflammatory cytokines, such as TNF-α, NF-kB, and IL-6, in the tissue were significantly attenuated, all of which complemented the beneficial effects of URO A in DOX-induced liver injury. In addition, URO A was able to alter the expression of caspase 3 and cytochrome c oxidase in the livers of rats that were subjected to DOX stress. These results showed that URO A reduced DOX-induced liver injury by reducing oxidative stress, inflammation, and apoptosis.

Detection of Adverse Drug Reactions in COVID-19 Hospitalized Patients in Saudi Arabia: A Retrospective Study by ADR Prompt Indicators.

Seeking an alternative approach for detecting adverse drug reactions (ADRs) in coronavirus patients (COVID-19) and enhancing drug safety, a retrospective study of six months was conducted utilizing an electronic medical record (EMR) database to detect ADRs in hospitalized patients for COVID-19, using "ADR prompt indicators" (APIs). Consequently, confirmed ADRs were subjected to multifaceted analyses, such as demographic attribution, relationship with specific drugs and implication for organs and systems of the body, incidence rate, type, severity, and preventability of ADR. The incidence rate of ADRs is 37%, the predisposition of organs and systems to ADR is observed remarkably in the hepatobiliary and gastrointestinal systems at 41.8% vs. 36.2%, p < 0.0001, and the classes of drugs implicated in the ADRs are lopinavir-ritonavir 16.3%, antibiotics 24.1%, and hydroxychloroquine12.8%. Furthermore, the duration of hospitalization and polypharmacy are significantly higher in patients with ADRs at 14.13 ± 7.87 versus 9.55 ± 7.90, p < 0.001, and 9.74 ± 5.51 versus 6.98 ± 4.36, p < 0.0001, respectively. Comorbidities are detected in 42.5% of patients and 75.2%, of patients with DM, and HTN, displaying significant ADRs, p-value < 0.05. This is a symbolic study providing a comprehensive acquaintance of the importance of APIs in detecting hospitalized ADRs, revealing increased detection rates and robust assertive values with insignificant costs, incorporating the hospital EMR database, and enhancing transparency and time effectiveness.

Colon-Targeted Therapy of Tacrolimus (FK506) in the Treatment of Experimentally Induced Colitis.

BACKGROUND/AIMS: Inflammatory bowel disease is a chronic or remitting/relapsing intestinal inflammation, which comprises Crohn's disease and ulcerative colitis (UC). Severe UC is a life-threatening condition that requires corticosteroids (CS) as a first-line rescue therapy. Some patients are refractory to CS and may require alternative immunosuppressive therapy. Oral tacrolimus (FK506), an immunosuppressive agent, has been reported to be effective in the management of severe refractory UC, but it can cause serious adverse effects. This work aims to study the effect of tacrolimus delivered by a colon-targeted delivery system (CTDS) in a dextran sulfate sodium (DSS)-induced animal model of colitis. MATERIALS AND METHODS: We developed and evaluated an oral CTDS of tacrolimus (FK506) loaded pH-dependent polymeric microspheres, composed of Eudragit® S100 as a pH-sensitive polymer using the oil-in-water emulsion method. The physicochemical properties and drug release profiles of these microparticles in gastrointestinal tract (GIT) conditions were examined. A DSS-induced colitis rat model was used to evaluate the potential remedial and in vivo distribution of microspheres. RESULTS: The pH-microspheres prevented a burst drug release in acidic pH conditions and showed sustained release at a colonic pH. The in vivo distribution study in the rat GIT demonstrated that pH-microspheres were successfully delivered to the inflamed colon. Moreover, it also demonstrated a significant decrease of disease activity and expression of proinflammatory cytokines, such as tumor necrosis factor α, interleukin-1ß (IL-1ß), and IL-6, and minimized the histological and morphometric changes. CONCLUSION: The results confirmed the efficacy of tacrolimus (FK506) CTDs in the management of DSS-induced colitis.

Correction to: Chemosensitizing and nephroprotective effect of resveratrol in cisplatin-treated animals.

[This corrects the article DOI: 10.1186/s12935-014-0152-2.].

Impact of thymoquinone on cyclosporine A pharmacokinetics and toxicity in rodents.

OBJECTIVES: Cyclosporine A (CsA) is an immunosupprsant drug used to prevent graft rejection and in the treatment of several autoimmune diseases. Thyomquinone (TQ), a bioactive component of Nigella sativa, has strong antioxidant properties and has been used in prevention of many toxicities, hence its protective effect and pharmacokinetic interactions with CsA was investigated in this study. METHODS: For bioavailability study, the rats were divided into four groups: TQ (PO, 10 mg/kg) was given alone for 7 days, then TQ plus CsA for another 5 days, CsA was given by two routes (po) and (IP) in a dose of 10 mg/kg 1 h after administration of TQ. Blood samples were taken at the 12th day at specified times, CsA level was determined by immune assays. The protective effect of TQ was studied. Blood samples for lab investigations and histopathology were taken at the 28th day. KEY FINDINGS: Thyomquinone reduced the bioavailability of oral CsA by around 32% (P > 0.05). However, bioavailability of IP administered CsA was not affected. Chronic administration of CsA increased concentrations of fasting glucose and Cystatin C and produced marked s kidney alteration of parenchyma which was reversed by concomitant administration of TQ. CONCLUSIONS: A potential drug interaction between TQ and CsA, which may reduced its oral bioavailability. Independently TQ caused significant attenuation of CsA induced renal toxicity and diabetogenic effect.

Characterization of the Antinociceptive Mechanisms of Khat Extract (Catha edulis) in Mice.

This study investigated the antinociceptive mechanisms of khat extract (100, 200, and 400 mg/kg, i.p.) in four pain models: two thermic (hot plate, tail-flick) and two chemical (acetic acid, formalin) models. Male mice were pretreated intraperitoneally (i.p.) with the opioid receptor blocker naloxone (5 mg/kg), the cholinergic antagonist atropine (2 mg/kg), the selective α1 blocker prazosin (1 mg/kg), the dopamine D2 antagonist haloperidol (1.5 mg/kg), or the GABAA receptor antagonist, bicuculline (1 mg/kg) 15 minutes prior to i.p. injection of khat extract (400 mg/kg). Khat extract reduced the nociceptive response of mice in the four pain tests. Naloxone significantly inhibited the antinociceptive effect of khat extract in the hot plate, tail-flick, and the first phase of formalin tests. Bicuculline significantly antagonized the antinociceptive effect of khat extract on the hot plate and tail-flick tests. Haloperidol significantly reversed the antinociceptive effect of khat extract on the tail-flick test and the first phase of formalin test. These results provide strong evidence that the antinociceptive activity of khat extract is mediated via opioidergic, GABAergic, and dopaminergic pathways. The mechanism of the antinociceptive action of khat may be linked to the different types of pain generated in animal models.

Dilemmas of the causality assessment tools in the diagnosis of adverse drug reactions.

IMPORTANCE: Basic essence of Pharmacovigilance is prevention of ADRs and its precise diagnosis is crucially a primary step, which still remains a challenge among clinicians. OBJECTIVE: This study is undertaken with the objective to scrutinize and offer a notion of commonly used as well as recently developed methods of causality assessment tools for the diagnosis of adverse drug reactions and discuss their pros and cons. EVIDENCE REVIEW: Overall 49 studies were recognized for all assessment methods with five major decisive factors of causality evaluation, all the information regarding reasons allocating causality, the advantages and limitations of the appraisal methods were extracted and scrutinized. FINDINGS: From epidemiological information a past prospect is designed and subsequent possibility merged this background information with a clue in the individual case to crop up with an approximation of causation. Expert judgment is typically based on the decisive factor on which algorithms are based, nevertheless in imprecise manner. The probabilistic methods use the similar principle; however connect probabilities to each measure. Such approaches are quite skeptical and liable to generate cloudy causation results. Causation is quite intricate to ascertain than correlation in Pharmacovigilance due to numerous inherent shortcomings in causality assessment tools. CONCLUSIONS AND RELEVANCE: We suggest that there is a need to develop a high quality assessment tool which can meticulously establish suitable diagnostic criteria for ADRs with universal acceptance to improvise the fundamental aspect of drug safety and evade the impending ADRs with the motive to convert Pharmacovigilance into a state of art.

Weaving together peer assessment, audios and medical vignettes in teaching medical terms.

OBJECTIVE: The current study aims at exploring the possibility of aligning peer assessment, audiovisuals, and medical case-report extracts (vignettes) in medical terminology teaching. In addition, the study wishes to highlight the effectiveness of audio materials and medical history vignettes in preventing medical students' comprehension, listening, writing, and pronunciation errors. The study also aims at reflecting the medical students' attitudes towards the teaching and learning process. METHODS: The study involved 161 medical students who received an intensive medical terminology course through audio and medical history extracts. Peer assessment and formative assessment platforms were applied through fake quizzes in a pre- and post-test manner. An 18-item survey was distributed amongst students to investigate their attitudes and feedback towards the teaching and learning process. Quantitative and qualitative data were analysed using the SPSS software. RESULTS: The students did better in the posttests than on the pretests for both the quizzes of audios and medical vignettes showing a t-test of -12.09 and -13.60 respectively. Moreover, out of the 133 students, 120 students (90.22%) responded to the survey questions. The students gave positive attitudes towards the application of audios and vignettes in the teaching and learning of medical terminology and towards the learning process. CONCLUSIONS: The current study revealed that the teaching and learning of medical terminology have more room for the application of advanced technologies, effective assessment platforms, and active learning strategies in higher education. It also highlights that students are capable of carrying more responsibilities of assessment, feedback, and e-learning.

The possible antianginal effect of allopurinol in vasopressin-induced ischemic model in rats.

The anti-anginal effects of allopurinol were assessed in experimental model rats of angina and their effects were evaluated with amlodipine. In the vasopressin-induced angina model, oral administration of allopurinol in dose of 10 mg/kg revealed remarkably analogous effects in comparison with amlodipine such as dose-dependent suppression of vasopressin-triggered time, duration and severity of ST depression. In addition, allopurinol produced dose dependent suppression of plasma Malondialdehyde (MDA) level, systolic blood pressure, cardiac contractility and cardiac oxygen consumption; while in contrast, amlodipine minimally suppressed the elevation of plasma MDA level. Endothelial NO synthase (eNOS) expression, serum nitrate were strikingly increased, however lipid profile was significantly reduced. Seemingly, allopurinol was found to be more potent than amlodipine - a calcium channel antagonist. To conclude, it was explicitly observed and verified that on the ischemic electrocardiography (ECG) changes in angina pectoris model in rats, allopurinol exerts a significant protective effects, reminiscent of enhancement of vascular oxidative stress, function of endothelial cells, improved coronary blood flow in addition to the potential enhancement in myocardial stress. Moreover, our findings were in conformity with several human studies.

Detection of adverse drug reactions by medication antidote signals and comparison of their sensitivity with common methods of ADR detection.

OBJECTIVE: To determine the PPVs of selected ten medication antidote signals in recognizing potential ADRs and comparison of their sensitivity with manual chart analysis, and voluntary reporting recognizing the same ADRs. METHOD: The inpatient EMR database of internal medicine department was utilized for a period of one year, adult patients prescribed at least one of the ten signals, were included in the study, recipient patients of antidote signals were assessed for the occurrence of an ADR by Naranjo's tool of ADR evaluation. PPVs of each antidote signal were verified. RESULT: PPV of Methylprednisolone and Phytonadione was 0.28, Metoclopramide and Potassium Chloride - 0.29, Dextrose 50%, Promethazine, Sodium Polystyrene and Loperamide - 0.30, Protamine and Acetylcysteine - 0.33. In comparison of confirmed ADRs of antidote signals with other methods, Dextrose 50%, Metoclopramide, Sodium Polystyrene, Potassium Chloride, Methylprednisolone and Promethazine seem to be extremely significant (P value > 0.0001), while ADRs of Phytonadione, Protamine, Acetylcysteine and Loperamide were insignificant. CONCLUSION: Antidote medication signals have definitive discerning evaluation value of ADRs over routine methods of ADR detection with a high detection rate with a minimum cost; Their integration with hospital EMR database and routine patient safety surveillance enhances transparency, time-saving and facilitates ADR detection.

Dimethylsulfoxide excerbates cisplatin-induced cytotoxicity in Ehrlich ascites carcinoma cells.

BACKGROUND: Cisplatin (CIS) is a potent antineoplastic agent with high therapeutic efficacy against many kinds of tumors. Its use is limited by its nephrotoxicity. The aim of this work was to minimize cisplatin effective dose and the possible reduction of its severe side effects. The present study was designed to assess the role of sulfur containing agent dimethyl sulfoxide (DMSO) on sensitization of mammary carcinoma, Ehrlich ascites carcinoma (EAC), to the action of cisplatin and at the same time the possible protective effect against cisplatin induced nephrotoxicity in experimental animals. METHODS: To evaluate these effects we have explored the cisplatin effect on the survival time of tumor-bearing animals, tumor weight, cisplatin cellular uptake, apoptosis induction and cell cycle distribution and renal function in presence and absence of DMSO. RESULTS: Cisplatin at dose of 4.5 mg/kg increased the mean survival time of tumor bearing mice to 37 days compared with tumor bearing control mice. Pretreatment of tumor bearing mice with DMSO 50 % (2 ml/kg equal to 1 gm/kg) 2 h. before cisplatin showed a significant increase in their mean survival time 43 days compared to cisplatin treated animals. DMSO pretreatment retained rat's serum urea and creatinine levels to normal compared to animals treated with cisplatin alone. CONCLUSION: DMSO pretreatment enhanced the cytotoxic activity of cisplatin against the growth of EAC in vivo and showed protective effects against cisplatin-induce nephrotoxicity.

Perceptions and knowledge regarding antimicrobial stewardship among clinicians in Jeddah, Saudi Arabia.

OBJECTIVES: To understand the perceptions, attitude, and prescribing practices of clinicians regarding antimicrobial resistance (AMR). METHODS: A multidisciplinary cross-sectional study comprising 447 clinicians of university, public, and private hospitals of Jeddah, Saudi Arabia was carried out from August to October 2014 using a self-administered questionnaire. RESULTS: Interestingly, 33% of the general physicians yielded to patient/parent's demand for the choice of antimicrobials (AMs) as compared with only 13.2% of the residents, and 4.3% of the specialists. In addition, expensive AMs are more often prescribed by the general physician (70.4%) in comparison with 26.4% residents and 30.4% of the specialists. However, no significant differences were observed between the knowledge and perceptions regarding the current scope of AM agents, as well as their use and misuse. Furthermore, dependability of specialist and residents seems to be significantly higher than general physicians on pocketbooks and smartphone for AM education sources. CONCLUSION: This study revealed that despite a clear concept of AMR, general physicians lacks consistency in prescribing aptitude and use of effective educational resources, while all respondents lacks dedication to follow the guidelines of AM use. This highlights the requirement of AM stewardship with decisive objective of reduction in AMR.

Chemosensitizing and nephroprotective effect of resveratrol in cisplatin -treated animals.

BACKGROUND: Cisplatin (CIS) is one of the most effective anticancer drug used in the treatment of several solid tumors .Its use is limited by its nephrotoxicity. The present study was designed to assess the role of a natural product resveratrol (RSVL) on sensitization of mammary carcinoma (Ehrlich ascites carcinoma) to the action of CIS and the possible protective effect against CIS-induced nephrotoxicity in rats. METHODS: The percent survival of female tumor bearing mice was used for determination the cytotoxic activity of CIS in the presence or the absence of RSVL. Uptake and cell cycle effect, serum creatinine (CREA), blood urea nitrogen (BUN), Reduced Glutathione (GSH) and histopatholgical examination of kidney tissues after CIS and/or RSVL therapy were also investigated. RESULTS: RSVL increased the intracellular level of CIS in EAC cells and there was a strong correlation between the high cellular level of CIS and its cytotoxicity. CIS at a dose level of 5 mg/kg increased the mean survival time of female tumor bearing mice to 25 days compared with 17 days for tumor-bearing control mice. Administration of RSVL at a dose level of 25 mg/kg simultaneously with CIS increased the mean survival time to 48 days with 60% survival of the tumor-bearing animals. Cell cycle analysis of tumor cells showed that CIS treatment decreases the proliferation index of tumor cells while in presence of RSVL there was more significant inhibitions. Also, CIS treatment caused increase in level of creatinine and blood urea with significant decrease in the GSH level. While, in the presence of RSVL, level of creatinine and blood urea restored to control level. CONCLUSION: This study suggests that RSVL could increase the cytotoxic activity of CIS and protect against its nephrotoxicity.

Amelioration of doxorubicin­induced cardiotoxicity by resveratrol.

Doxorubicin (DOX), is a highly active anticancer agent, but its clinical use is limited by its severe cardiotoxic side­effects associated with increased oxidative stress and apoptosis. Resveratrol (RSVL) is a naturally occurring polyphenolic compound (trans-3,5,4'-trihydroxystilbene) found primarily in root extracts of the oriental plant Polygonum cuspidatum and of numerous additional plant species. It has recently been shown that RSVL has a number of beneficial effects in different biological systems, which include anti-oxidant, antineoplastic, anticarcinogenic, cardioprotective and antiviral effects. In this study, we examined whether RSVL has protective effects against DOX­induced free radical production and cardiotoxicity in male rats. The tested dose of DOX (20 mg/kg) caused a significant increase in the serum activities of the cardiac enzymes lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) and the level of malondialdehyde (MDA) in the heart tissue. However, there was a significant decrease in the glutathione level in the heart tissue. Simultaneous treatment of rats with RSVL [10 mg/kg, intraperitoneal (i.p.) injection] reduced the activity of LDH and CPK and significantly reduced MDA production in the heart. The total antioxidant capacity was increased following RSVL administration. Electron microscopy examination of the heart tissue showed that DOX treatment results in massive fragmentation and lysis of the myofibrils, and that mitochondria show either vacuolization or complete loss of the cristae. Simultaneous treatment with RSVL ameliorated the effect of DOX administration on cardiac tissue, with cardiomyocytes appearing normal compared to the control samples, and mitochondria retaining their normal structure.

Appraisal of antimicrobial prescribing practices of governmental and non-governmental dentists for hospitals in the western region of Saudi Arabia.

OBJECTIVE: To scrutinize the knowledge, attitude, and antimicrobial practices in Saudi Arabian Dentistry. METHODS: In this cross-sectional survey of dentists, a self-administered questionnaire comprising of 61 questions was dispersed to the participants randomly, which included their professional profile, awareness of the current scope of antimicrobial resistance, prescribing practice, frequency of antimicrobial prescription, and sources of continuing education of antimicrobials. The study took place in the Faculty of Dentistry, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia between February and April 2013. RESULTS: Knowledge and awareness concerning specific antimicrobials, with specific oral cavity lesion was 78% for the students and interns, 80% for residents, and 95.3% for specialists. Approximately 89% of the students, interns and residents, and 98.4% of the specialists endorsed indiscriminate use of antibiotics. In addition, 93.4% of students, 90% of interns and residents, and 90.6% of specialists agreed that lack of health education is one of the contributors to overuse of antimicrobials. Moreover, 91.9% of the interns, 80% of residents, and 75.5% of specialists preferred amoxicillin + clavulanate as their first choice; however, a wide variation in the dosage frequency, and duration was observed. CONCLUSION: Participants are well aware of the significance of antimicrobial resistance, and considered that judicious use of antimicrobials is highly imperative to restrain this fiery predicament. Divergence was demonstrated between specialists and residents in prescribing practices. Institutional antimicrobial guideline was not interesting to all the respondents. This highlights the need for incessant instructive intervention in order to accomplish the prime objective of retreating antimicrobial resistance.

Adverse drug reactions in hospitalized pediatric patients of Saudi Arabian University Hospital and impact of pharmacovigilance in reporting ADR.

OBJECTIVES: Children are more vulnerable to ADRs, and this susceptibility is compounded due to hospitalization. There is a lack of local data regarding the potential risk of ADRs in hospitalized pediatric patients. Therefore, this study is designed to identify the frequent nature, severity of adverse drug reactions, drugs implicated and factors influencing ADRs. METHODS: Intensive monitoring study of ADRs was done in hospitalized pediatric patients of King Abdulaziz University Hospital, Jeddah from January to December 2011, with an analogous retrospective study for the preceding year to determine incidence rate, demographic aspects, causality appraisal, polypharmacy, body organs/systems involved and drugs implicated in ADR. Comparison of the two data was done to determine the impact of pharmacovigilance. RESULTS: Incidence rate of ADRs in retrospective study was (4.50%) and (8.2%) in prospective study. ADR was more in patients who received 5-6 drugs, which was (15.5%) in retrospective study and (22.1%) in prospective study. Regarding age, it was the highest in patients of 0-1 year of age which was (40.7%) in retrospective study and (38.8%) in prospective study. Anti-infective agents were the most frequently involved in ADR (40.8%) in prospective study and (48.2%) and retrospective study. This study also demonstrated that, there was high susceptibility of the skin to the ADR which was (37%) in retrospective study and (42.9%) in prospective study. None of the ADRs proved to be fatal. CONCLUSION: Well premeditated intensive monitoring approach in pharmacovigilance amplifies the ADR detection, which can persuade healthcare providers into more drug safety.

Impact of pharmacovigilance on adverse drug reactions reporting in hospitalized internal medicine patients at Saudi Arabian teaching hospital.

OBJECTIVES: To determine the incidence, diversity of adverse drug reactions (ADRs), and impact of pharmacovigilance on reporting it. METHODS: This prospective and retrospective study was carried out in the Department of Medicine, King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia between January to December 2011 in 600 patients of ADR. Data regarding age and gender distribution of the patients, incidence rate, drugs, body systems/organs involved in ADR, time of occurrence of adverse drug reactions, total number of drugs administered, and impact of pharmacovigilance on finding the incidence rate of ADR were recorded. Comparison of the 2 data was carried out to determine the impact of pharmacovigilance. RESULTS: Incidence rate of ADRs in retrospective study was 3.1% and 5.5% in the prospective study. The highest incidence of ADR (retrospective 15% and prospective 14.5%) was observed in both groups in patients receiving more than 10 drugs. The frequency of ADR in relation to age in both groups was highest in patients of age >60 years; it was 52.7% in retrospective study and 54.5% in prospective study. Antibiotics were the more frequently involved in ADR, (48.5% in prospective study and 36.9% in retrospective study). The system most commonly involved in ADR was gastrointestinal tract 47.4% in retrospective study and 57.6% in prospective study. None of the ADR proved to be fatal. CONCLUSION: Low incidence of hospitalized ADR in our study (5.5%) is due to lack of awareness in healthcare professionals in reporting ADR. Undoubtedly, pharmacovigilance brought more patients with ADR to record.