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.

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.

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.

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.

Polypharmacy, potentially serious clinically relevant drug-drug interactions, and inappropriate medicines in elderly people with type 2 diabetes and their impact on quality of life.

The aim of the study is to investigate the patterns of polypharmacy, clinical-relevant drug-drug interactions (DDIs), and potentially inappropriate medicines (PIMs), and whether polypharmacy, potential serious clinically-relevant DDIs, or PIMs can be associated with low quality of life (QoL) index scores of older adults with type 2 diabetes (T2D). A cross-sectional study was conducted using data of 670 elderly T2D sub-cohort from a nationwide pharmacy-based intensive monitoring study of inception cohort of T2D in Portugal. 72.09% were found on polypharmacy (≥5 medicines). Participants on polypharmacy were mostly females (P = .0115); more obese (P = .0131); have more comorbid conditions (P < .0001); more diabetes complications (P < .0001); and use more of glucose lowering drugs (P = .0326); insulin (P < .0001); chronic medicines (P < .0001); and have higher diabetes duration (P = .0088) than those without polypharmacy. 10.59% of the participants were found to have potential serious clinically relevant DDIs. The most frequent drug-combinations were angiotensin-converting enzyme (ACE) inhibitors with angiotensin-receptor blockers (ARBs), aspirin with Selective serotonin reuptake inhibitors (SSRIs), and clopidogrel with calcium channel blockers. PIMs are found in 36.11% of the participants. The most common PIMs were benzodiazepines, long-acting sulfonylureas, and iron overdose. The adjusted multivariate models show that Polypharmacy, PIMs, and potential serious clinically relevant DDIs were associated with lower QoL index scores (OR 1.80 95% CI 1.15-2.82), (OR 1.57 95% CI 1.07-2.28), and (OR 1.34 95% CI 0.73-2.48) respectively. The study shows that polypharmacy, potential serious clinical-relevant DDIs, and PIMs may correlate with risk of reduced health related QoL outcome of older adults with T2D.

Fast and reliable ICP-MS quantification of palladium and platinum-based drugs in animal pharmacokinetic and biodistribution studies.

Palladium-(Pd)-based drugs are emerging as alternatives to platinum (Pt) anticancer chemotherapeutics, which increases the need for efficient and suitable procedures of Pd analysis in reduced amounts of pre-clinical animal samples. Herein, an ICP-MS (inductively coupled plasma-mass spectrometry) method was developed and validated for simple and fast analysis of Pd/Pt-based drugs in 11 distinct biological matrices (adipose tissue, muscle, liver, kidney, spleen, testis, heart, lungs, brain, blood and serum). The critical variables affecting sample preparation and Pd/Pt extraction were optimized using two-level (2k) factorial and central composite designs. Biological samples (50 mg) were digested in closed tubes with a screw cap, using a 3 : 1 (v/v) mixture of nitric acid (900 µL) and hydrochloric acid (300 µL) for 60 min in a 90 °C water bath. Full method validation using in-house materials showed a LOD of 0.001 µg L-1, linear dynamic range from 0.025-10 µg L-1 (R2 = 0.9999 for Pd; R2 = 0.9998 for Pt), good repeatability (CV: 0.02-1.9%) and intermediate precision (CV: 0.52-1.53%) for both the studied metals. The accuracy ranged from 83.5-105.1% considering microwave-assisted digestion as the reference method. The developed and validated method allows the processing of hundreds of biological samples simultaneously, with low reagent and sample consumption. Therefore, the method is highly suitable for analysis of novel Pd/Pt-based drugs in pharmaco-toxicokinetic and biodistribution animal studies that involve a large number of multi-organ samples.

Anti-inflammatory effect of lycopene on carrageenan-induced paw oedema and hepatic ischaemia-reperfusion in the rat.

The regular intake of tomatoes or its products has been associated with a reduced risk of chronic diseases and these effects have been mainly attributed to lycopene. Here, we evaluated the anti-inflammatory properties of lycopene and its protective effects on organ injury in two experimental models of inflammation. In order to study the effects of lycopene in local inflammation, a carrageenan-induced paw oedema model in rats was performed. Lycopene was administered as an acute (1, 10, 25 or 50 mg/kg, intraperitoneally, 15 min before carrageenan injection) and chronic treatment (25 or 50 mg/kg per d, 14 d). Inflammation was assessed by the measurement of paw volume increase after 6 h. Lycopene significantly inhibited paw oedema formation at two doses (25 and 50 mg/kg) in both acute and repeated administration. The effect of lycopene on liver inflammation was evaluated in a liver ischaemia-reperfusion (I/R) model. Rats were subjected to 45 min of ischaemia of three-quarters of the liver followed by 2 h of reperfusion. In this model, lycopene was administered daily at two doses (25 and 50 mg/kg) during the 14 d that preceded the experiments. Repeated administration of lycopene reduced liver injury induced by I/R, as demonstrated by the reduction of the increase in liver injury markers (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and gamma-glutamyl transferase) and attenuation of liver tissue lipoperoxidation was evidenced by a decrease in malondialdehyde production. The present results show that lycopene exhibited local anti-inflammatory activity and also attenuated liver injury induced by I/R. We speculate that lycopene administration might be useful in the pharmacological modulation of inflammatory events.

Anticancer activity of palladium-based complexes against triple-negative breast cancer.

Treatment of triple-negative breast carcinoma (TNBC) remains an unmet medical need with no targeted therapy available to date. Accounting for 10-30% of all human breast cancer tumors, this mammary carcinoma subtype has a particularly poor prognosis owing to its high metastatic potential, aggressive biology and limited pharmacological treatment options. Platinum chemotherapeutics are the mainstay therapy in patients with TNBC but their clinical use is limited by severe toxicity and acquired resistance. Palladium-based complexes are appealing alternative metal-based drugs because of significant similarities regarding structure and coordination chemistry with the platinum agents. This review summarizes the knowledge gathered so far on 121 Pd(II) complexes, emphasizing their anticancer activity and putative pharmacological targets toward TNBC.

The opposing effects of the flavonoids isoquercitrin and sissotrin, isolated from Pterospartum tridentatum, on oral glucose tolerance in rats.

The effect of an aqueous extract of Pterospartum tridentatum on the blood glucose levels of normal Wistar rats was investigated in a situation of oral glucose challenge. The extract at 300 mg/kg showed an antihyperglycaemic effect in the first 30 min after glucose challenge but then the blood glucose levels rose above those of the control group, indicating the presence of compounds with different effects on glucose tolerance. Nine compounds of isoflavone and flavonol skeletons were identified in the extract by HPLC-ESI-MS(n), four of them being identified for the first time in this species. The isoflavone sissotrin and the flavonol derivative, isoquercitrin, were selected for the oral glucose tolerance test. Isoquercitrin (100 mg/kg) showed time-dependent antihyperglycaemic activity by delaying the post-oral glucose load glycaemic peak at 30 min, as did the sodium-dependent glucose transporter inhibitor phloridzin (100 mg/kg). In contrast, sissotrin (100 mg/kg) showed an opposite effect, impairing glucose tolerance. In conclusion, these preliminary results indicate that the effect of the extract on blood glucose may be either antihyperglycaemic or hyperglycaemic. Additionally, as far as is known, these are the first in vivo results on the acute antihyperglycaemic potential of isoquercitrin.

Hemin reduces inflammation associated with TNBS-induced colitis.

PURPOSE: Hemin is a heme-oxygenase inducer, which can confer anti-inflammatory, cytoprotective, and antiapoptotic effects. These properties are beneficial therapeutical effects to inflammatory bowel disease (IBD). IBD is a worldwide health problem characterized by chronic inflammation of intestinal epithelium, which promotes intestinal and extraintestinal symptomatology. Current treatment only induces and maintains the patient in remission and results in many side effects. The research of other pharmacologic approaches is crucial to the treatment of IBD. The aim of this study is to evaluate the effect of hemin in the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model. MATERIALS AND METHODS: Male CD-1 mice with TNBS-induced colitis were treated with a daily dose of hemin 5 mg/kg body weight/day and 10 mg/kg body weight/day intraperitoneal, during 4 days. The evaluated parameters were fecal hemoglobin, alkaline phosphatase (ALP), myeloperoxidase, tumor necrosis factor-α, interleukin (IL)-1ß, IL-10, histopathologic analysis, urea, creatinine, and alanine aminotransferase. RESULTS: The hemin-treated mice presented a decrease in fecal hemoglobin, ALP, and proinflammatory cytokine concentrations compared to the TNBS group. Histopathology analysis confirmed the decrease in lesion extension produced by hemin. CONCLUSION: These findings suggest that hemin treatment reduces hemorrhagic focus, intestinal damage, tissue inflammation, and lesion extension associated with experimental colitis.