Drug-drug interactions and inappropriate medicines impact on glycemic control and kidney function in older adults with diabetes-attending specialty care institution.

PURPOSE: To describe and assess the impact of polypharmacy, and its potential adverse reactions; serious clinically relevant drug-drug interactions (DDIs) and inappropriate medicines (PIMs) on glycemic target, and kidney function in a sample of older adults with type 2 diabetes (T2D). METHODS: Cross-sectional study was performed in a real-world database including 444 elderly people with T2D from the Portuguese Diabetes Association, aged ≥ 65 years, and registered in 2018. DDIs were analyzed using Micromedex drug-interaction platform and PIMs identified using STOPP criteria version-2. RESULTS: Polypharmacy was identified in 43.6% of patients. This group of patients has shown to be more females (50 vs. 39.6%, P=0.0208), higher HbA1c targets (P=0.0275), longer diabetes duration (66.4 vs. 54.4%, P=0.0019), more hypertensive (87 vs. 62.9%, P<0.0001), using more insulin (38.1 vs. 26%, P=0.0062), sulfonylureas (37.1 vs. 15.6%, P<0.0001), GLP-1 receptor-agonists (9.7 vs. 3.6%, P=0.0077), metformin-DPP-4 inhibitors (41.2 vs. 29.2%, P=0.0081), and SGLT2 inhibitors (19 vs. 9.6%, P=0.0040). A total of 8.7% of patients had potentially serious clinically relevant DDIs, mainly due to interacting medicine pairs dexamethasone and fluoroquinolones. Furthermore, 23.4% had PIMs, and cardiovascular medicines accounted for largest therapeutic group associated. Polypharmacy found to be associated with twofold greater odds of having HbA1c ≤8%, whereas PIMs associated with 2.5-fold greater odds of having HbA1c ≤9%, and 5.5-folds greater odds of having severe kidney function. CONCLUSIONS: These findings suggested that there is a potential association between polypharmacy and PIMs and altered glycemic control, and PIMs with the deterioration of kidney function.

Overtreatment and undertreatment in a sample of elderly people with diabetes.

AIMS: In older adults with type 2 diabetes (T2D), overtreatment remains prevalent and undertreatment ignored. The main objective is to estimate the prevalence and examine factors associated with potential overtreatment and undertreatment. METHOD: Observational study conducted within an administrative database of older adults with T2D who registered in 2018 at the Portuguese Diabetes Association. Participants were categorized either as potentially overtreated (HbA1c ≤ 7.5%), appropriately on target (HbA1c ≥7.5 to ≤9%), or potentially undertreated (HbA1c > 9%). RESULTS: The study included 444 participants: potential overtreatment and undertreatment were found in 60.5% and 12.6% of the study population. Taking the patients on target as a comparator, the group of potentially overtreated showed to be more men (61.3% vs 52.2%), less-obese (34.1% vs 39.2), higher cardiovascular diseases (13.7% vs 11%), peripheral vascular diseases (16.7% vs 12.8%), diabetic foot (10% vs 4.5%), and severe kidney disease (5.2% vs 4.5%). Conversely, the potentially undertreated participants were more women (64.2% vs 47.7%), obese (49% vs 39.2%), had more dyslipidemia (69% vs 63.1%), peripheral vascular disease (14.2% vs 12.8%), diabetic foot (8.9% vs 4.5%), and infections (14.2% vs 11.9%). The odds of potential overtreatment were mostly decreased by 59% of women, 73.5% in those with retinopathy, and 86.3% in insulin, 65.4% sulfonylureas, and 66.8% in SGLT2 inhibitors users. Contrariwise, an increase in the odds of potential undertreatment was more than 4.8 times higher in insulin, and more than 3.1 times higher in sulfonylureas users. CONCLUSION: Potential overtreatment and undertreatment in older adults with T2D in routine clinical practice should guide the clinicians to balance the use of newer oral antidiabetic agents considering its safety profile regarding hypoglycemia.

The cardiac output optimisation following liver transplant (COLT) trial: a feasibility randomised controlled trial.

BACKGROUND: Perioperative goal directed fluid therapy (GDFT) has been shown to reduce postoperative complications following major surgery; this intervention has not been formally evaluated in the setting of liver transplantation. METHODS: We conducted a prospective trial of GDFT following liver transplantation randomising patients with liver cirrhosis to either 12 h of GDFT using non-invasive cardiac output monitoring or standard care (SC). The primary outcome was feasibility. Secondary outcomes included survival, postoperative complications (Clavien-Dindo), quality of life (by EQ-5D-5L) and resource use. Trial specific follow up occurred at 90 and 180 days after surgery. RESULTS: The study was feasible. Of 224 eligible patients, 122 were approached, 114 consented to participate and 60 were enrolled into the trial. The mean (SD) volume of IV crystalloid administered to the GDFT group during the 12-h study period was 3968 (2073) ml for the GDFT group and 2510 (1026) ml for the SC group. As regards secondary outcomes there was no difference in survival or overall complication rates. There was no significant difference in quality of life scores and resource use between the groups. CONCLUSION: A randomised study of GDFT following liver transplantation is feasible. A post-trial stakeholder meeting supported proceeding with a full multi-centre trial.

Thiadiazolidinone-8 Ameliorates Inflammation Associated with Experimental Colitis in Mice.

Thiadiazolidinone-8 (TDZD-8) is an effective thiadiazolidinone derivate that is able to suppress the expression of inflammatory cytokines; it also presents tissue protective actions by glycogen synthase kinase (GSK)-3ß inhibition, promoting thus an anti-inflammatory effect. Since inflammatory bowel disease is a chronic disease with reduced quality of life, where currently available therapies are only able to induce or maintain the patient in remission, it is crucial to investigate new pharmacological approaches. The main objective of this study was to evaluate the effect of TDZD-8 in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Male CD-1 mice with TNBS-induced colitis were treated with a daily dose of TDZD-8 5 mg/kg/day IP during 4 days. The anti-inflammatory properties of TDZD-8 in the TNBS-induced colitis were confirmed by suppression of pro-inflammatory mediators, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and myeloperoxidase, as well as by the significant increase of the anti-inflammatory cytokine, IL-10. These treated mice also presented a reduction in fecal hemoglobin and alkaline phosphatase, suggesting a beneficial effect of TDZD-8. Furthermore, renal and hepatic biomarkers remained stabilized after treatment. In conclusion, TDZD-8 reduces the inflammatory response associated with TNBS-induced colitis in mice, and modulation of GSK-3ß seems to be an interesting pharmacological target in colitis.

European community pharmacists practice in tackling influenza.

Background: In many European countries, flu vaccination coverage rates are below the 75% target. During the COVID-19 pandemic, many pharmacists around Europe were involved as vaccine administrators and demonstrated positive results in improving vaccine uptake. This paper explores the challenges, accomplishments, and best practices of various European pharmacists' associations in administering vaccines and positively contributing to public health. Methods: Eight pharmacists representing various associations from different countries across Europe (Italy, Belgium, Poland, Portugal, France, and Germany) convened to discuss their role as vaccination providers, the advantages, and strategies for improvement, and to identify barriers and gaps in the vaccination administration process, especially focusing on the administration of seasonal flu vaccines. Results: Currently, 15 European countries allow community pharmacists to dispense and administer flu vaccines. Among the ones that attended the meeting, Portugal initiated the flu immunization program at the pharmacy earliest, before the COVID era, but in other countries, the process started only in the last couple of years. Initial hesitancy and reluctance by other HCPs or institutions were overcome as the pilot projects showed positive and cost-effective public health results. Today, pharmacists are considered crucial professional figures to provide immunization services against COVID-19, the flu, and other vaccine-preventable diseases, and pursue important public health goals.Key takeaways to enhance the pharmacist's role in providing immunization services against vaccine-preventable diseases include improving interaction with policymakers and the public, generating real-world evidence highlighting public health benefits, and ensuring ongoing professional education and training for pharmacists. Conclusion: Vaccinating pharmacists are gaining recognition of their role and the benefits derived from their broader involvement in the healthcare system, including immunization programs. Further efforts are needed in each country for an adequate recognition of the profession and a broader utilization of pharmacy services to exploit the benefit of immunization, especially against the flu.

The integration of rapid qualitative research in clinical trials: reflections from the ward-based goal-directed fluid therapy (GDFT) in acute pancreatitis feasibility trial.

BACKGROUND: There has been an increase in the integration of qualitative studies in randomised controlled trials. The purpose of this article is to reflect on our experience of carrying out a rapid qualitative study during a feasibility trial of goal-directed fluid therapy (GDFT) in patients with acute pancreatitis, including our sharing of emerging findings and the use of these findings by the trial team. METHODS: The study was designed as a rapid feedback evaluation and combined interviews with staff and patients who took part in the trial. FINDINGS: The rapid qualitative study pointed to common problems in trial recruitment among multiple sites, where lack of engagement of clinical teams across sites might impact negatively on patient recruitment. The article describes how the use of rapid feedback loops can be used as the trial is ongoing to inform changes in implementation. It also covers the potential challenges of working rapidly and collaborative with the trial team. CONCLUSIONS: Rapid feedback evaluations can be used to generate findings across all stages of trial design and delivery. Additional research is required to explore the implementation of this research design in other settings and trial designs.

Perioperative redox changes in patients undergoing hepato-pancreatico-biliary cancer surgery.

BACKGROUND: Tissue injury induces inflammation and the surgical stress response, which are thought to be central to the orchestration of recovery or deterioration after surgery. Enhanced formation of reactive oxygen and nitrogen species accompanies the inflammatory response and triggers separate but integrated reduction/oxidation (redox) pathways that lead to oxidative and/or nitrosative stress (ONS). Quantitative information on ONS in the perioperative period is scarce. This single-centre exploratory study investigated the effects of major surgery on ONS and systemic redox status and their potential associations with postoperative morbidity. METHODS: Blood was collected from 56 patients at baseline, end of surgery (EoS) and the first postoperative day (day-1). Postoperative morbidity was recorded using the Clavien-Dindo classification and further categorised into minor, moderate and severe. Plasma/serum measures included markers of lipid oxidation (thiobarbituric acid-reactive substances; TBARS, 4-hydroxynonenal; 4-HNE, 8-iso-prostaglandin F2⍺; 8-isoprostanes). Total reducing capacity was measured using total free thiols (TFTs) and ferric-reducing ability of plasma (FRAP). Nitric oxide (NO) formation/metabolism was measured using cyclic guanosine monophosphate (cGMP), nitrite, nitrate and total nitroso-species (RxNO). Interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-⍺) were measured to evaluate inflammation. RESULTS: Both oxidative stress (TBARS) and nitrosative stress (total nitroso-species) increased from baseline to EoS (+14%, P = 0.003 and +138%, P < 0.001, respectively), along with an increase in overall reducing capacity (+9%, P = 0.03) at EoS and protein-adjusted total free thiols (+12%, P = 0.001) at day-1 after surgery. Nitrite, nitrate and cGMP concentrations declined concomitantly from baseline to day-1. Baseline nitrate was 60% higher in the minor morbidity group compared to severe (P = 0.003). The increase in intraoperative TBARS was greater in severe compared to minor morbidity (P = 0.01). The decline in intraoperative nitrate was more marked in the minor morbidity group compared to severe (P < 0.001), whereas the cGMP decline was greatest in the severe morbidity group (P = 0.006). CONCLUSION: In patients undergoing major HPB surgery, intraoperative oxidative and nitrosative stress increased, with a concomitant increase in reductive capacity. Baseline nitrate was inversely associated with postoperative morbidity, and the hallmarks of poor postoperative outcome include changes in both oxidative stress and NO metabolism.

Effect of post-operative goal-directed fluid therapy (GDFT) on organ function after orthotopic liver transplantation: Secondary outcome analysis of the COLT randomised control trial.

BACKGROUND: Goal-directed fluid therapy (GDFT) has been shown to reduce the complications following a variety of major surgical procedures, possibly mediated by improved organ perfusion and function. We have shown that it is feasible to randomise patients to GDFT or standard fluid management following liver transplant in the cardiac-output optimisation following liver transplantation (COLT) trial. The current study compares end organ function in patients from the COLT trial who received GDFT in comparison to those receiving standard care (SC) following liver transplant. METHODS: Adult patients with liver cirrhosis undergoing liver transplantation were randomised to GDFT or SC for the first 12 h following surgery as detailed in a published trial protocol. GDFT protocol was based on stroke volume (SV) optimisation using 250 ml crystalloid boluses. Total fluid administration and time to extubation were recorded. Hourly SV and cardiac output (CO) readings were recorded from the non-invasive cardiac output monitoring (NICOM) device in both groups. Pulmonary function was assessed by arterial blood gas (ABG) and ventilatory parameters. Lung injury was assessed using PaO2:FiO2 ratios and calculated pulmonary compliance. The KDIGO score was used for determining acute kidney injury. Renal and liver graft function were assessed during the post-operative period and at 3 months and 1-year. RESULTS: 60 patients were randomised to GDFT (n = 30) or SC (n = 30). All patients completed the 12 h intervention period. GDFT group received a significantly higher total volume of fluid during the 12 h trial intervention period (GDFT 5317 (2335) vs. SC 3807 (1345) ml, p = 0.003); in particular crystalloids (GDFT 3968 (2073) vs. SC 2510 (1027) ml, p = 0.002). There was no evidence of significant difference between the groups in SV or CO during the assessment periods. Time to extubation, PaO2: FIO2 ratios, pulmonary compliance, ventilatory or blood gas measurements were similar in both groups. There was a significant rise in serum creatinine from baseline (77 µmol/L) compared to first (87 µmol/L, p = 0.039) and second (107 µmol/L, p = 0.001) post-operative days. There was no difference between GDFT and SC in the highest KDIGO scores for the first 7 days post-LT. At 1-year follow-up, there was no difference in need for renal replacement therapy or graft function. CONCLUSIONS: In this randomised trial of fluid therapy post liver transplant, GDFT was associated with an increased volume of crystalloids administered but did not alter early post-operative pulmonary or renal function when compared with standard care.

Ward based goal directed fluid therapy (GDFT) in acute pancreatitis (GAP) trial: A feasibility randomised controlled trial.

BACKGROUND: Goal-directed fluid therapy (GDFT) reduces complications in patients undergoing major general surgery. There are no reports of cardiac output evaluation being used to optimise the fluid administration for patients with acute pancreatitis (AP) in a general surgery ward. METHOD: 50 patients with AP were randomised to either ward-based GDFT (n = 25) with intravenous (IV) fluids administered based on stroke volume optimisation protocol or standard care (SC) (n = 25), but with blinded cardiac output evaluation, for 48-h following hospital admission. Primary outcome was feasibility. RESULTS: 50 of 116 eligible patients (43.1%) were recruited over 20 months demonstrating feasibility. 36 (72%) completed the 48-h of GDFT; 10 (20%) discharged within 48-h and 4 withdrawals (3 GDFT, 1 SC). Baseline characteristics were similar with only 3 participants having severe disease (6%, 1 GDFT, 2 SC). Similar volumes of IV fluids were administered in both groups (GDFT 5465 (1839) ml, SC 5211 (1745) ml). GDFT group had a lower heart rate, blood pressure and respiratory rate and improved oxygen saturations. GDFT was not associated with any harms. There was no evidence of difference in complications of AP (GDFT 24%, SC 32%) or in the duration of stay in intensive care (GDFT 0 (0), SC 0.7 (3) days). Length of hospital stay was 5 (2.9) days in GDFT and 6.3 (7.6) in SC groups. CONCLUSION: Ward-based GDFT is feasible and shows a signal of possible efficacy in AP in this early-stage study. A larger multi-site RCT is required to confirm clinical and cost effectiveness.

A cross-sectional survey to map Clinical Pharmacy Education and Practice in Europe.

Background Clinical activities provided by pharmacists are increasing worldwide, including in Europe. However, an overview of clinical pharmacy education and practice is needed. Aim To map clinical pharmacy (CP) education and practice among European countries. Method A cross-sectional web-based survey led by the Education Committee of the European Society of Clinical Pharmacy (ESCP) was conducted. The survey comprised three domains focusing on: undergraduate education, postgraduate education, and practice. A multi-phased validation process was undertaken, attributing levels of evidence according to the number of information sources for each country. Triangulation was used to seek within country consensus. Main outcome measures included the number of hours of education in CP; existence of a specialization in CP and activities delivered in practice. Results Data from 40 European countries were included (response rate 95.2%). Most respondents (86.8%) agreed with the ESCP definition of CP. Almost every country (94.9%) reported CP topics at the undergraduate level [median number = 65 h/semester (IQR: 2.0-5.6)], including practical teaching [median = 30.0% (IQR: 17.0-42.0)]. At postgraduate level, 92.5% of countries reported PhD programmes including CP and 65.0% mentioned the existence of specific CP master/diploma degrees. Continuous professional development (CPD) courses were also reported by 63.9% of respondents. More than half the countries (52.5%; n = 21) recognized CP as an area of specialization, which for 60.0% of participants was applied solely in the hospital setting. Conclusion Although CP is embedded in education and practice in European countries, there is wide variability in education and practice patterns.

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice.

Pd2Spm is a dinuclear palladium(II)-spermine chelate with promising anticancer properties against triple-negative breast cancer (TNBC), a breast carcinoma subset with poor prognosis and limited treatment options. The present study evaluated the in vitro and in vivo anticancer effects of Pd2Spm compared to the reference metal-based drug cisplatin. Triple-negative breast cancer MDA-MB-231 cells, non-cancerous MCF-12A breast cells and chorioallantoic membrane (CAM) assay were used for antiproliferative, antimigratory and antiangiogenic studies. For an in vivo efficacy study, female CBA nude mice with subcutaneously implanted MDA-MB-231 breast tumors were treated with Pd2Spm (5 mg/kg/day) or cisplatin (2 mg/kg/day) administered intraperitoneally during 5 consecutive days. Promising selective antiproliferative activity of Pd2Spm was observed in MDA-MB-231 cells (IC50 values of 7.3-8.3 µM), with at least 10-fold lower activity in MCF-12A cells (IC50 values of 89.5-228.9 µM). Pd2Spm inhibited the migration of MDA-MB-231 cells, suppressed angiogenesis in CAM and decreased VEGF secretion from MDA-MB-231 cells with similar potency as cisplatin. Pd2Spm-treated mice showed a significant reduction in tumor growth progression, and tumors evidenced a reduction in the Ki-67 proliferation index and number of mitotic figures, as well as increased DNA damage, similar to cisplatin-treated animals. Encouragingly, systemic toxicity (hematotoxicity and weight loss) observed in cisplatin-treated animals was not observed in Pd2Spm-treated mice. The present study reports, for the first time, promising cancer selectivity, in vivo antitumor activity towards TNBC and a low systemic toxicity of Pd2Spm. Thus, this agent may be viewed as a promising Pd(II) drug candidate for the treatment of this type of low-prognosis neoplasia.

Protective role of peroxisome proliferator-activated receptor-ß/δ in septic shock.

RATIONALE: Peroxisome proliferator-activated receptor (PPAR)-ß/δ is a transcription factor that belongs to the PPAR nuclear hormone receptor family, but the role of PPAR-ß/δ in sepsis is unknown. OBJECTIVES: We investigated the role of PPAR-ß/δ in murine models of LPS-induced organ injury and dysfunction and cecal ligation and puncture (CLP)-induced polymicrobial sepsis. METHODS: Wild-type (WT) and PPAR-ß/δ knockout (KO) mice and C57BL/6 mice were subjected to LPS for 16 hours. C57BL/6 mice received the PPAR-ß/δ agonist GW0742 (0.03 mg/kg intravenously, 1 h after LPS) or GW0742 plus the PPAR-ß/δ antagonist GSK0660 (0.1 mg/kg intravenously, 30 min before LPS). CD-1 mice subjected to CLP received GW0742 or GW0742 plus GSK0660. MEASUREMENTS AND MAIN RESULTS: In PPAR-ß/δ KO mice, endotoxemia exacerbated organ injury and dysfunction (cardiac, renal, and hepatic) and inflammation (lung) compared with WT mice. In C57BL/6 mice subjected to endotoxemia, GW0742 significantly (1) attenuated organ (cardiac and renal) dysfunction and inflammation (lung); (2) increased the phosphorylation of Akt and glycogen synthase kinase (GSK)-3ß; (3) attenuated the increase in extracellular signal-regulated kinase (ERK)1/2 and signal transducer and activator of transcription (STAT)-3 phosphorylation; and (4) attenuated the activation of nuclear factor (NF)-κB and the expression of inducible nitric oxide synthase (iNOS). In CD-1 mice subjected to CLP, GW0742 improved 10-day survival. All the observed beneficial effects of GW0742 were attenuated by the PPAR-ß/δ antagonist GSK0660. CONCLUSIONS: PPAR-ß/δ protects against multiple organ injury and dysfunction, and inflammation caused by endotoxic shock and improves survival in polymicrobial sepsis by a mechanism that may involve activation of Akt and inhibition of GSK-3ß and NF-κB.

A feasibility randomised controlled trial of targeted oxygen therapy in mechanically ventilated critically ill patients.

BACKGROUND: Despite oxygen being the commonest drug administered to critically ill patients we do not know which oxygen saturation (SpO2) target results in optimal survival outcomes in those receiving mechanical ventilation. We therefore conducted a feasibility randomised controlled trial in the United Kingdom (UK) to assess whether it would be possible to host a larger national multi-centre trial to evaluate oxygenation targets in mechanically ventilated patients. METHODS: We set out to recruit 60 participants across two sites into a trial in which they were randomised to receive conservative oxygenation (SpO2 88-92%) or usual care (control - SpO2 ≥96%). The primary outcome was feasibility; factors related to safety and clinical outcomes were also assessed. RESULTS: A total of 34 patients were recruited into the study until it was stopped due to time constraints. A number of key barriers to success were identified during the course of the study. The conservative oxygenation intervention was feasible and appeared to be safe in this small patient cohort and it achieved wide separation of the median time-weighted average (IQR) SpO2 at 91% (90-92%) in conservative oxygenation group versus 97% (96-97%) in control group. CONCLUSION: Whilst conservative oxygenation was a feasible and safe intervention which achieved clear group separation in oxygenation levels, the model used in this trial will require alterations to improve future participant recruitment rates in the UK.

Portuguese Authorship in Published Clinical Trials: Differences in Industry and Investigator Initiated Trials.

INTRODUCTION: The aim of this study was to investigate the Portuguese authorship in publications resulting from trials initiated by the industry or investigators and run in Portugal. MATERIAL AND METHODS: Clinical trials with Portuguese institutions as sponsor or recruiting centers, and registered in four clinical trial registries, in the last 14 years, were assessed. Publications of completed trials, from both the initiative of the industry and investigatorswere screened and compared. RESULTS: The percentage of published trials initiated by industry and investigators was similar (28.0%). However, the percentage of completed investigator-initiated trials (43.6%) was lower when compared to industry trials (69.7%). There was a higher percentage of Portuguese authorship in published investigator-initiated trials when compared with industry-initiated trials (47.1% vs 8.5%, respectively). Moreover, industry-initiated trials with Portuguese authors were published in journals with lower journal impact factor when compared with those published without authorship of Portuguese investigators. Oncology was the therapeutic area with the highest number of clinical trial registrations and publications. However, in publications with Portuguese authors, industry Initiated trials mainly focused on neurology while investigator-initiated trials had a higher number of papers in the fields of gastroenterology and infection diseases. Published trials with Portuguese authorship, initiated by the industry or investigators, also targeted different populations and had different purposes. In both cases, no significant differences were observed in terms of the journal impact factor or in the alignment of the published randomized trials with the respective reporting guidelines. DISCUSSION: When compared with previous publications, this study showed an increasing trend in the number of clinical trials in Portugal, published within similar timeframes, after trial conclusion. Even though both industry and investigator trials are published within the standards for reporting trials, the low number of Portuguese authorships in industry publications might underline the need for invigorating these independent clinical trials in Portugal by capacitating and empowering national clinical research teams. CONCLUSION: This study confirmed that even though all registered trials had the involvement of Portuguese institutions as a recruiting center, not all the published trials had Portuguese investigators as authors, mainly those initiated by the industry.

Introdução: Este estudo teve por objetivo investigar a autoria Portuguesa em publicações que resultem de ensaios clínicos iniciados pela indústria e por investigadores, que tenham decorrido em Portugal. Material e Métodos: Quatro plataformas de registo de ensaios clínicos foram utilizadas para encontrar ensaios clínicos tendo instituições Portuguesas como promotor ou centro de recrutamento nos últimos 14 anos. Foram analisadas e comparadas as publicações dos estudos completos, da iniciativa da indústria e de investigadores Resultados: A percentagem de ensaios da iniciativa da indústria e de investigadores que são publicados era semelhante (~ 28,0%). Porém, a percentagem de ensaios completos da iniciativa de investigadores era mais baixa (43,6%) quando comparada com os ensaios completos da indústria (69,7%). Existiu uma maior percentagem de autores portugueses em ensaios publicados da iniciativa do investigador quando comparado com os ensaios da iniciativa da indústria (47,1% vs 8,5%). Para além disso, ensaios da iniciativa da indústria com autores portugueses foram publicados em jornais com fatores de impacto inferiores quando comparados com aqueles publicados sem autores portugueses. A oncologia foi a área terapêutica com maior número de ensaios registados e publicados. No entanto, em publicações com autores Portugueses, a indústria focou-se sobretudo na neurologia e os investigadores em gastroenterologia e doenças infeciosas. Ensaios publicados com autores portugueses, iniciados tanto pela indústria como por investigadores, focaram-se em populações diferentes e têm propósitos diferentes. Em ambos os casos, não foram encontradas diferenças estatisticamente significativas no fator de impacto dos jornais, nem no alinhamento dos ensaios aleatorizados publicados com as normas sobre escrita de artigos científicos. Discussão: Quando comparado com publicações anteriores, este estudo mostrou uma tendência de crescimento no número de ensaios clínicos em Portugal, sendo publicados em intervalos de tempo semelhantes após a sua conclusão. Embora os ensaios publicados da iniciativa da indústria e de investigadores estejam alinhados com as normas sobre escrita de artigos científicos, o baixo número de autorias nacionais em publicações de ensaios da indústria, sublinha a necessidade de revigorar os ensaios clínicos da iniciativa de investigadores através da capacitação e emancipação das equipas de investigação nacionais. Conclusão: Apesar de todos os ensaios registados terem o envolvimento de instituições portuguesas como centros de recrutamento, nem todos os ensaios têm autores portugueses nas publicações, principalmente aqueles que são iniciados pela indústria.

Preclinical Pharmacokinetics and Biodistribution of Anticancer Dinuclear Palladium(II)-Spermine Complex (Pd2Spm) in Mice.

Palladium-based compounds are regarded as potential analogs to platinum anticancer drugs with improved properties. The present study assessed the pharmacokinetics and biodistribution of a dinuclear palladium(II)-spermine chelate (Pd2Spm), which has previously been shown to possess promising in vitro activity against several therapy-resistant cancers. Using inductively coupled plasma-mass spectrometry, the kinetic profiles of palladium/platinum in serum, serum ultrafiltrate and tissues (kidney, liver, brain, heart, lungs, ovaries, adipose tissue and mammary glands) were studied in healthy female Balb/c mice after a single intraperitoneal bolus injection of Pd2Spm (3 mg/kg bw) or cisplatin (3.5 mg/kg bw) between 0.5 and 48 h post-injection. Palladium in serum exhibited biphasic kinetics with a terminal half-life of 20.7 h, while the free palladium in serum ultrafiltrate showed a higher terminal half-life than platinum (35.5 versus 31.5 h). Palladium was distributed throughout most of the tissues except for the brain, with the highest values in the kidney, followed by the liver, lungs, ovaries, adipose tissue and mammary glands. The in vitro cellular accumulation was also evaluated in breast cancer cells, evidencing a passive diffusion as a mechanism of Pd2Spm's cellular entry. This study reports, for the first time, the favorable pharmacokinetics and biodistribution of Pd2Spm, which may become a promising pharmacological agent for cancer treatment.

Spiro-ß-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium.

The high burden of malaria and HIV/AIDS prevents economic and social progress in developing countries. A continuing need exists for development of novel drugs and treatment regimens for both diseases in order to address the tolerability and long-term safety concerns associated with current treatment options and the emergence of drug resistance. We describe new spiro-ß-lactam derivatives with potent (nM) activity against HIV and Plasmodium and no activity against bacteria and yeast. The best performing molecule of the series, BSS-730A, inhibited both HIV-1 and HIV-2 replication with an IC50 of 13 ± 9.59 nM and P. berghei hepatic infection with an IC50 of 0.55 ± 0.14 µM with a clear impact on parasite development. BSS-730A was also active against the erythrocytic stages of P. falciparum, with an estimated IC50 of 0.43 ± 0.04 µM. Time-of-addition studies showed that BSS-730A potentially affects all stages of the HIV replicative cycle, suggesting a complex mechanism of action. BSS-730A was active against multidrug-resistant HIV isolates, with a median 2.4-fold higher IC50 relative to control isolates. BSS-730A was equally active against R5 and X4 HIV isolates and displayed strong synergism with the entry inhibitor AMD3100. BSS-730A is a promising candidate for development as a potential therapeutic and/or prophylactic agent against HIV and Plasmodium.

Recovery of oral glucose tolerance by Wistar rats after treatment with Coreopsis tinctoria infusion.

Infusions of Coreopsis tinctoria flowering tops have traditionally been used in Portugal to control hyperglycaemia but no pharmacological or toxicological studies have been reported until now. The chalcones marein and okanin were isolated from the aqueous extract, together with the 2S-3',4',7,8-tetrahydroxyflavanone. The content of marein in extracts was determined by HPLC-UV and the radical scavenging capacity evaluated by the DPPH method (EC(50) = 21 microg/mL). Glucose intolerance was induced by a single intraperitoneal injection of streptozotocin in saline (40 mg/Kg). After three weeks of oral treatment with C. tinctoria extract (500 mg/Kg/day) the animals were no longer glucose-intolerant (p > 0.05). Additionally, this oral treatment caused no hepatotoxicity in the rats, as determined by blood alanine and aspartate transaminases. A single administration of extract had no effect on oral glucose tolerance in normal Wistar rats. The extract also had no effect on insulin secretion by MIN6 cells. In conclusion, C. tinctoria infusion is able to abolish the streptozotocin-induced glucose-intolerance in rats after three weeks of oral treatment by a mechanism other than induction of insulin secretion. The recovery of beta-pancreatic function mediated by an antioxidant mechanism is a possibility that deserves further investigation.

Antihyperglycaemic and protective effects of flavonoids on streptozotocin-induced diabetic rats.

The antihyperglycaemic effect of eight standard flavonoids, previously identified in the ethanol extract of the claimed antidiabetic plant Genista tenera, was evaluated on streptozotocin (STZ)-induced diabetic Wistar rats. The aglycones apigenin, chrysoeriol and genistein, the monoglucosides apigenin 7-O-glucoside, luteolin 7-O-glucoside and genistein 7-O-glucoside and the diglycosides rutin and luteolin 7,3'-di-O-glucoside were administered i.p. for 7 days (4 mg/kg b.w./day). The protective effect of these compounds over liver and kidneys of STZ-diabetic models was also evaluated by the determination of seric AST, ALT and urea levels. After 7 days of treatment, apigenin, chrysoeriol and genistein significantly lowered the blood glucose levels of diabetic animals; this effect was more pronounced (P < 0.01) in the oral glucose tolerance test. Glucose tolerance was also significantly improved in the rutin (P < 0.01) and in the genistein 7-O-glucoside (P < 0.05) treated groups. In addition, almost all the tested compounds effectively protected the liver and kidneys against STZ-induced damage in rats.

Primary health care policy and vision for community pharmacy and pharmacists in Portugal.

The central role of the Portuguese National Health Service (P-NHS) guarantees virtually free universal coverage. Key policy papers, such as the National Health Plan and the National Plan for Patient Safety have implications for pharmacists, including an engagement in medicines reconciliation. These primary health care reform, while not explicitly contemplating a role for pharmacists, offer opportunities for the involvement of primary care pharmacists in medicines management. Primary care pharmacists, who as employees of the P-NHS work closely with an interdisciplinary team, have launched a pilot service to manage polypharmacy in people living with multimorbidities, involving potential referral to community pharmacy. Full integration of community pharmacy into primary health care is challenging due to their nature as private providers, which implies the need for the recognition that public and private health sectors are mutually complementary and may maximize universal health coverage. The scope of practice of community pharmacies has been shifting to service provision, currently supported by law and in some cases, including the needle and syringe exchange program and generic substitution, remunerated. Key changes envisaged for the future of pharmacists and their integration in primary care comprise the development and establishment of clinical pharmacy as a specialization area, peer clinician recognition and better integration in primary care teams, including full access to clinical records. These key changes would enable pharmacists to apply their competence in medicines optimization for improved patient outcomes.

Therapeutic effects of IkB kinase inhibitor during systemic inflammation.

Animal models of inflammatory diseases support the idea that nuclear factor κB (NF-κB) activation plays a pathophysiological role and is widely implicated in multiple organ dysfunction (MOD). Indeed, the inhibition of the IκB kinase (IKK) complex, involved in the NF-κB pathway, can represent a promising approach to prevent MOD. The present work employed a rat model of systemic inflammation to investigate the preventive effects of Inhibitor of IKK complex (IKK16). In male Wistar rats, systemic inflammation was induced by a tail vein injection of lipopolysaccharides (LPS challenge; 12 mg/kg). Treatment with IKK16 (1 mg/kg body weight) was administered, by tail vein, 15 min post-LPS. Age- and sex-matched healthy rats and LPS rats without treatment were used as controls. At 24 h post-IKK16 treatment, serum enzyme levels indicative of liver, kidney, pancreas and muscle function were evaluated by biochemical analysis, and RT-PCR technique was used to analyze gene expression of pro-inflammatory cytokines. Hemodynamic parameters were also considered to assess the LPS-induced inflammation. IKK16 treatment yielded a strong therapeutic effect in preventing LPS-induced elevation of serological enzyme levels, attenuating hepatic, renal, pancreatic and muscular dysfunction after LPS challenge. Moreover, as expected, LPS promoted a significantly overexpression of TNF-α, IL-6 and IL-1ß in the heart, kidney, and liver; which was diminished by IKK16 treatment. The present study provides convincing evidence that selective inhibition of the IκB kinase complex through the action of IKK16, plays a protective role against LPS-induced multiple organ dysfunction by reducing the acute inflammatory response induced by endotoxin exposure.