Drug information-seeking behaviour among Jordanian physicians: a cross-sectional study.

Background: Due to the huge number of drugs available and the rapid growth and change in drug information, healthcare professionals, especially physicians, frequently require reliable, easily accessible, rapid, and accurate reference sources to obtain the necessary drug information. Several sources of information are available for physicians to use and select from; however, the information-seeking behaviour of healthcare providers is varied, and this process can be challenging. Objectives: In this study, Jordanian physicians were approached to evaluate the drug information they require, the sources of information they use, the perceived credibility of the sources, and the challenges they face when searching for the most accurate and current information about drugs. Methods: This is an observational, cross-sectional study. A self-administered questionnaire was distributed to practising physicians in Jordan using a convenience sampling method (purposive sampling followed by snowball sampling) regardless of their speciality, age, gender, seniority, or place of employment. Results: Three hundred and eighty physicians participated in the study. Most participants responded that they performed drug information searches on a weekly (155, 40.8%) or a daily basis (150, 39.5%). The drug-related information that physicians most frequently searched for concerned dosage regimens and adverse drug events. The majority of surveyed doctors (97.9%) reported using online websites to acquire drug information; UpToDate®, Medscape and Drugs.com were the most frequently used online databases, although many participants did not consider online sources to be the most reliable source. The most prevalent and recurrent challenges encountered concerned an inability to access subscription-only journals and websites (56.6%), difficulty identifying trusted and credible sources (41.8%) and the enormous number of available sources (35.3%). However, these challenges were less of a problem for physicians who currently work or have previously worked in academia (p < 0.001). Conclusion: This study demonstrated that Jordanian physicians frequently use online websites to look for drug information and all doctors face challenges throughout this process particularly those with no experience in academia. This suggests that being in academia makes the process of information-seeking easier which highlights the need for academics to transfer their knowledge and experience to their non-academic colleagues and the upcoming generations of physicians.

Generic switching: Do future physicians in Jordan have enough knowledge and a positive attitude?

Background: Generic switching is a policy that has shown success in minimising pharmaceutical costs. It has also been used to mitigate recurrent and sudden drug shortages. Not all countries have policies that allow pharmacists to switch to generic drugs independently. In Jordan, only pharmacists at Ministry of Health hospitals automatically switch to generics if doctors had not already done INN prescribing. Objectives: This study targeted medical students to assess their experience with generic switching as patients, their knowledge of the subject as students, and their attitude towards it as future prescribers and policymakers. Methods: This is a descriptive, cross-sectional study conducted online. Eligibility criteria were being a fourth, fifth, or sixth-year medical school student enrolled at any of the six Jordanian universities. The questionnaire was developed by the researchers after a careful review of the relevant literature. Results: Three hundred and ninety students responded to the online questionnaire. Most participants were females (244, 62.6%), senior students in their final (6th) year (162, 41.5%) and with very good academic achievement (166, 42.6%). The highest knowledge scores concerned patient rights (0.73/1.00), followed by knowledge about monitoring after generic switching (0.66/1.00), and patients with known drug allergies (0.66/1.00). Almost half of the participants believe that pharmacists should not be given the right to do generic switching and only 16% stated that they would choose generic drugs if they needed treatment in the future. Multivariate linear regression analysis showed that significant predictors of knowledge were gender, GPA, and family income. No correlations were found between participants' knowledge scores and their attitudes towards giving pharmacists the right to independently switch drugs, or whether they would accept a substitute from pharmacists rather than having to refer to the physician. Conclusion: Medical students in Jordan lack sufficient knowledge about generic switching. Students need to be more aware of the current policies and regulations of this practice, and the role of each healthcare worker involved in it. They also need to have a more positive attitude toward generic drugs and generic switching practice to facilitate its future implementation.

A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice.

Metabolic endotoxemia has been suggested to play a role in the pathophysiology of metaflammation, insulin-resistance and ultimately type-2 diabetes mellitus (T2DM). The role of endogenous antimicrobial peptides (AMPs), such as the cathelicidin LL-37, in T2DM is unknown. We report here for the first time that patients with T2DM compared to healthy volunteers have elevated plasma levels of LL-37. In a reverse-translational approach, we have investigated the effects of the AMP, peptide 19-2.5, in a murine model of high-fat diet (HFD)-induced insulin-resistance, steatohepatitis and T2DM. HFD-fed mice for 12 weeks caused obesity, an impairment in glycemic regulations, hypercholesterolemia, microalbuminuria and steatohepatitis, all of which were attenuated by Peptide 19-2.5. The liver steatosis caused by feeding mice a HFD resulted in the activation of nuclear factor kappa light chain enhancer of activated B cells (NF-ĸB) (phosphorylation of inhibitor of kappa beta kinase (IKK)α/ß, IκBα, translocation of p65 to the nucleus), expression of NF-ĸB-dependent protein inducible nitric oxide synthase (iNOS) and activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, all of which were reduced by Peptide 19-2.5. Feeding mice, a HFD also resulted in an enhanced expression of the lipid scavenger receptor cluster of differentiation 36 (CD36) secondary to activation of extracellular signal-regulated kinases (ERK)1/2, both of which were abolished by Peptide 19-2.5. Taken together, these results demonstrate that the AMP, Peptide 19-2.5 reduces insulin-resistance, steatohepatitis and proteinuria. These effects are, at least in part, due to prevention of the expression of CD36 and may provide further evidence for a role of metabolic endotoxemia in the pathogenesis of metaflammation and ultimately T2DM. The observed increase in the levels of the endogenous AMP LL-37 in patients with T2DM may serve to limit the severity of the disease.

Household Drug Stockpiling and Panic Buying of Drugs During the COVID-19 Pandemic: A Study From Jordan.

The coronavirus disease that emerged in 2019 (COVID-19) has affected health, societies and economies. Policies that have been imposed by different countries to slow the spread of the disease, including national lockdowns, curfews, border closures and enforcement of social distancing measures have disturbed the drug supply chain and resulted in drug shortages. Uncertainty concerning the pandemic has also led to the panic buying of drugs and the stockpiling of drugs in households, which has amplified the problem. In this cross-sectional study, a self-developed questionnaire was distributed online in order to a) assess the practice of household drug stockpiling prior to the national lockdown in Jordan, b) investigate the factors affecting it and c) measure peoples' knowledge about the consequences of this behaviour. Results from this study show that drug purchasing was reported by 44.3% of the participants and was most common among participants from non-medical backgrounds (336, 75.7%) or those who have chronic diseases (261, 58.8%) and taking chronic supplements (282, 63.5%) regardless of their age, gender, living area or the possession of health insurance. Analgesics and antipyretics were the most frequently purchased drugs (225, 70.5%) and anticipation of their need was the most common reason for purchasing drugs (231, 52.0%). Buyers were also less aware, when compared to non-buyers, that panic buying and drug stockpiling may lead to drug shortages (204, 45.9% vs 325, 58.1%) and that this behaviour can pose a health hazard, especially to children (221, 47.5% vs 342, 61.2%). Our study shows that panic buying of drugs and household drug stockpiling were common in Jordan during the COVID-19 pandemic and this was related to participants' medical knowledge and educational backgrounds. Therefore, educating the general population regarding rational drug use is urgently needed. This is also a compelling case for the development of national guidelines for drug management that target the general population and healthcare personnel, especially pharmacists, to avoid drug shortages during crises.

RvE1 Attenuates Polymicrobial Sepsis-Induced Cardiac Dysfunction and Enhances Bacterial Clearance.

The development of cardiac dysfunction caused by microbial infection predicts high mortality in sepsis patients. Specialized pro-resolving mediators (SPMs) mediate resolution of inflammation in many inflammatory diseases, and are differentially expressed in plasma of sepsis patients. Here, we investigated whether the levels of SPMs are altered in the murine septic heart following polymicrobial sepsis-induced cardiac dysfunction. Ten weeks-old male C57BL/6 mice were subjected to polymicrobial sepsis induced by cecal ligation and puncture (CLP), which is a clinically relevant sepsis model receiving analgesics, antibiotics, and fluid resuscitation. CLP caused a significant systolic dysfunction assessed by echocardiography. The hearts were subjected to LC-MS/MS based lipid mediator profiling. Many SPMs were significantly reduced in septic hearts, among which RvE1 had a ~93-fold reduction. Treatment of CLP mice with synthetic RvE1 (1 µg/mouse i.v.) at 1 h after CLP increased peritoneal macrophages number, particularly MHC II- macrophages. RvE1 reduced pro-inflammatory gene expression (interleukin-1ß, interleukin-6, and CCL2) in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs) in vitro. RvE1 attenuated cardiac dysfunction in septic mice and increased cardiac phosphorylated Akt; decreased cardiac phosphorylated IκB kinase α/ß, nuclear translocation of the NF-κB subunit p65, extracellular signal-regulated kinase 1/2, and c-Jun amino-terminal kinases 1/2. Most notably, RvE1 treatment reduced peritoneal bacterial load and promoted phagocytosis activity of BMDMs. In conclusion, cardiac SPMs, particularly RvE1, are substantially reduced in mice with polymicrobial sepsis. Delayed therapeutic administration of RvE1 to mice with polymicrobial sepsis attenuates the cardiac dysfunction through modulating immuno-inflammatory responses. In addition to the above effects, the ability to enhance bacterial clearance makes RvE1 an ideal therapeutic to reduce the sequalae of polymicrobial sepsis.

Bruton's Tyrosine Kinase Inhibition Attenuates the Cardiac Dysfunction Caused by Cecal Ligation and Puncture in Mice.

Sepsis is one of the most prevalent diseases in the world. The development of cardiac dysfunction in sepsis results in an increase of mortality. It is known that Bruton's tyrosine kinase (BTK) plays a role in toll-like receptor signaling and NLRP3 inflammasome activation, two key components in the pathophysiology of sepsis and sepsis-associated cardiac dysfunction. In this study we investigated whether pharmacological inhibition of BTK (ibrutinib 30 mg/kg and acalabrutinib 3 mg/kg) attenuates sepsis associated cardiac dysfunction in mice. 10-week old male C57BL/6 mice underwent CLP or sham surgery. One hour after surgery mice received either vehicle (5% DMSO + 30% cyclodextrin i.v.), ibrutinib (30 mg/kg i.v.), or acalabrutinib (3 mg/kg i.v.). Mice also received antibiotics and an analgesic at 6 and 18 h. After 24 h, cardiac function was assessed by echocardiography in vivo. Cardiac tissue underwent western blot analysis to determine the activation of BTK, NLRP3 inflammasome and NF-κB pathway. Serum analysis of 33 cytokines was conducted by a multiplex assay. When compared to sham-operated animals, mice subjected to CLP demonstrated a significant reduction in ejection fraction (EF), fractional shortening (FS), and fractional area change (FAC). The cardiac tissue from CLP mice showed significant increases of BTK, NF-κB, and NLRP3 inflammasome activation. CLP animals resulted in a significant increase of serum cytokines and chemokines (TNF-α, IL-6, IFN-γ, KC, eotaxin-1, eotaxin-2, IL-10, IL-4, CXCL10, and CXCL11). Delayed administration of ibrutinib and acalabrutinib attenuated the decline of EF, FS, and FAC caused by CLP and also reduced the activation of BTK, NF-κB, and NLRP3 inflammasome. Both ibrutinib and acalabrutinib significantly suppressed the release of cytokines and chemokines. Our study revealed that delayed intravenous administration of ibrutinib or acalabrutinib attenuated the cardiac dysfunction associated with sepsis by inhibiting BTK, reducing NF-κB activation and the activation of the inflammasome. Cytokines associated with sepsis were significantly reduced by both BTK inhibitors. Acalabrutinib is found to be more potent than ibrutinib and could potentially prove to be a novel therapeutic in sepsis. Thus, the FDA-approved BTK inhibitors ibrutinib and acalabrutinib may be repurposed for the use in sepsis.

The Septic Heart: Current Understanding of Molecular Mechanisms and Clinical Implications.

Septic cardiomyopathy is a key feature of sepsis-associated cardiovascular failure. Despite the lack of consistent diagnostic criteria, patients typically exhibit ventricular dilatation, reduced ventricular contractility, and/or both right and left ventricular dysfunction with a reduced response to volume infusion. Although there is solid evidence that the presence of septic cardiomyopathy is a relevant contributor to organ dysfunction and an important factor in the already complicated therapeutic management of patients with sepsis, there are still several questions to be asked: Which factors/mechanisms cause a cardiac dysfunction associated with sepsis? How do we diagnose septic cardiomyopathy? How do we treat septic cardiomyopathy? How does septic cardiomyopathy influence the long-term outcome of the patient? Each of these questions is interrelated, and the answers require a profound understanding of the underlying pathophysiology that involves a complex mix of systemic factors and molecular, metabolic, and structural changes of the cardiomyocyte. The afterload-related cardiac performance, together with speckle-tracking echocardiography, could provide methods to improve the diagnostic accuracy and guide therapeutic strategies in patients with septic cardiomyopathy. Because there are no specific/causal therapeutics for the treatment of septic cardiomyopathy, the current guidelines for the treatment of septic shock represent the cornerstone of septic cardiomyopathy therapy. This review provides an up-to-date overview of the current understanding of the pathophysiology, summarizes the evidence of currently available diagnostic tools and treatment options, and highlights the importance of further urgently needed studies aimed at improving diagnosis and investigating novel therapeutic targets for septic cardiomyopathy.

Linagliptin Attenuates the Cardiac Dysfunction Associated With Experimental Sepsis in Mice With Pre-existing Type 2 Diabetes by Inhibiting NF-κB.

The mortality rate of patients who develop sepsis-related cardiac dysfunction is high. Many disease conditions (e.g., diabetes) increase the susceptibility to infections and subsequently sepsis. Activation of the NF-κB pathway plays a crucial role in the pathophysiology of sepsis-associated cardiac dysfunction and diabetic cardiomyopathy. The effect of diabetes on outcomes in patients with sepsis is still highly controversial. We here hypothesized that type 2 diabetes (T2DM) augments the cardiac (organ) dysfunction associated with sepsis, and that inhibition of the NF-κB pathway with linagliptin attenuates the cardiac (organ) dysfunction in mice with T2DM/sepsis. To investigate this, 10-week old male C57BL/6 mice were randomized to receive normal chow or high fat diet (HFD), 60% of calories derived from fat). After 12 weeks, mice were subjected to sham surgery or cecal ligation and puncture (CLP) for 24 h. At 1 hour after surgery, mice were treated with linagliptin (10 mg/kg, i.v.), IKK-16 (1 mg/kg, i.v.), or vehicle (2% DMSO, 3 ml/kg, i.v.). Mice also received analgesia, fluids and antibiotics at 6 and 18 h after surgery. Mice that received HFD showed a significant increase in body weight, impairment in glucose tolerance, reduction in ejection fraction (%EF), and increase in alanine aminotransferase (ALT). Mice on HFD subjected to CLP showed further reduction in %EF, increase in ALT, developed acute kidney dysfunction and lung injury. They also showed significant increase in NF-κB pathway, iNOS expression, and serum inflammatory cytokines compared to sham surgery group. Treatment of HFD-CLP mice with linagliptin or IKK-16 resulted in significant reductions in (i) cardiac, liver, kidney, and lung injury associated with CLP-sepsis, (ii) NF-κB activation and iNOS expression in the heart, and (iii) serum inflammatory cytokine levels compared to HFD-CLP mice treated with vehicle. Our data show that pre-existing type 2 diabetes phenotype worsens the organ dysfunction/injury associated with CLP-sepsis in mice. Most notably, inhibition of NF-κB reduces the organ dysfunction/injury associated with sepsis in mice with pre-existing T2DM.