Chronic kidney disease progression in diabetic patients: Real world data in general practice.

Aims: the aim of the study was to analyze glomerular filtration ratio (GFR) changes in diabetic patients assisted by General Practitioners (GPs) evaluating the risk factors related to glomerular function. Methods: patients with diabetes with at least three recorded values of creatinine were recruited in the study and GFR values were estimated. The quarterly percentage change in GFR for each patient was estimated. Nephrotoxic drugs were identified, and glucose-lowering drugs use was described. Linear regression analyses were performed to identify eGFR changes predictors. Results: a total of 545 patients with diabetes were selected. According to the last eGFR values 64 (11.7 %) patients were classified in G1 stage, 277 (50,8 %) in G2, 175 (32.1 %) in G3a, 25 (4.6 %) in G3b and only 4 (0.7 %) in G4. Patients treated with at least one glucose-lowering drugs were 479 (87.9 %), most of them with biguanides (67.0 %). At least one nephrotoxic drug prescription was recorded in 524 (96.1 %) patients; proton pump inhibitors (74.7 %) and NSAIDs (71.6 %) were the most prescription classes. Heart failure, diabetes duration and preserved GFR values were related to reduced eGFR values. Conclusions: patients with diabetes should be more carefully observed regardless of kidney risk factors and GFR values in clinical practice.

Effects of genistein aglycone in glucocorticoid induced osteoporosis: A randomized clinical trial in comparison with alendronate.

Glucocorticoid-induced osteoporosis (GIO) complicates the clinical management of patients subjected to long-term glucocorticoid use. This study explored the effects of genistein on bone loss in a randomized double-blind alendronate-controlled trial in postmenopausal women with GIO. 200 postmenopausal women (taking at least 5 mg of prednisone equivalents) since 3 months, or more, and expected to continue for at least other 12 months, were randomized to receive genistein (54 mg/day daily) or alendronate (70 mg once a week) for 24 months. Both groups received also Calcium and Vitamin D3 supplementation. Median bone mineral density (BMD) at the antero-posterior lumbar spine significantly increased from 0.75 g/cm2 at baseline to 0.77 g/cm2 at 1 year and 0.79 g/cm2 at 2 years in alendronate-treated patients and from 0.77 g/cm2 at baseline to 0.79 g/cm2 at 12 months and to 0.80 g/cm2 at 24 months in genistein recipients. No difference was observed between the two treatments. Median BMD at the femoral neck increased from 0.67 g/cm2 at baseline to 0.68 g/cm2 at 1 year and 0.69 g/cm2 at 2 years in alendronate-treated patients and from 0.68 g/cm2 at baseline to 0.70 g/cm2 at 12 months and to 0.71 g/cm2 at 24 months in genistein recipients. No difference was observed between alendronate and genistein groups in BMD. Regarding bone markers genistein and alendronate statistically decreased c-terminal telopeptide, while osteocalcin, bone-ALP, and sclerostin showed greater changes in genistein treated patients. This randomized clinical trial suggests that genistein aglycone represents an additional therapeutic option for patients with GIO.

Corrigendum: Activation of A2A receptor by PDRN reduces neuronal damage and stimulates WNT/ß-catenin driven neurogenesis in spinal cord injury.

[This corrects the article DOI: 10.3389/fphar.2018.00506.].

Corrigendum: Exploiting curcumin synergy with natural products using quantitative analysis of dose-effect relationships in an experimental in vitro model of osteoarthritis.

[This corrects the article DOI: 10.3389/fphar.2019.01347.].

The "Diabetes Comorbidome": A Different Way for Health Professionals to Approach the Comorbidity Burden of Diabetes.

(1) Background: The disease burden related to diabetes is increasing greatly, particularly in older subjects. A more comprehensive approach towards the assessment and management of diabetes' comorbidities is necessary. The aim of this study was to implement our previous data identifying and representing the prevalence of the comorbidities, their association with mortality, and the strength of their relationship in hospitalized elderly patients with diabetes, developing, at the same time, a new graphic representation model of the comorbidome called "Diabetes Comorbidome". (2) Methods: Data were collected from the RePoSi register. Comorbidities, socio-demographic data, severity and comorbidity indexes (Cumulative Illness rating Scale CIRS-SI and CIRS-CI), and functional status (Barthel Index), were recorded. Mortality rates were assessed in hospital and 3 and 12 months after discharge. (3) Results: Of the 4714 hospitalized elderly patients, 1378 had diabetes. The comorbidities distribution showed that arterial hypertension (57.1%), ischemic heart disease (31.4%), chronic renal failure (28.8%), atrial fibrillation (25.6%), and COPD (22.7%), were the more frequent in subjects with diabetes. The graphic comorbidome showed that the strongest predictors of death at in hospital and at the 3-month follow-up were dementia and cancer. At the 1-year follow-up, cancer was the first comorbidity independently associated with mortality. (4) Conclusions: The "Diabetes Comorbidome" represents the perfect instrument for determining the prevalence of comorbidities and the strength of their relationship with risk of death, as well as the need for an effective treatment for improving clinical outcomes.

Appropriateness of Antibiotic Prescribing in Hospitalized Children: A Focus on the Real-World Scenario of the Different Paediatric Subspecialties.

Background: Antibiotics are prescribed for children both in hospital and community settings, particularly at preschool age. Italy shows a high rate of inappropriate antibiotic prescriptions which may represent a serious problem in the hospital scenario. Thus, the aim of this study was to investigate appropriateness of antibiotic prescribing in the context of different paediatric subspecialties in a hospital setting. Methods: Antibiotics prescribing was retrospectively analysed in paediatric patients (0-18 years) admitted in the emergency paediatrics, general paediatrics, paediatric nephrology and rheumatology units between January and December 2019. Patients were stratified by age in neonates, infants, toddlers, children and adolescents. Assessments were conducted by trained local assessors and appropriateness was classified as appropriate, inappropriate and not assessable. Results: Empirical antibiotics were mainly prescribed following a diagnosis of respiratory, gastrointestinal and/or urinary infection. A total of 825 antibiotic prescriptions were recorded in the three subspecialties; 462 antibiotic prescriptions (56%) out of 825 were assessed as inappropriate and 55 prescriptions (6.7%) were not assessable. Inappropriateness considerably varied within subspecialties: the risk of inappropriate antibiotic prescribing was higher in emergency paediatrics and general paediatric than in children, according to age. Ceftriaxone and clarithromycin were the most inappropriate prescribed antibiotics in the emergency paediatrics whereas amoxicillin/clavulanic acid represented the most inappropriate antibiotic prescribed in general paediatrics. Conclusion: The present data may be useful in order to reduce inappropriate antibiotic prescribing in the paediatric setting; antibiotic stewardship and clinical improvement programs in hospital paediatric care are strongly recommended.

Beta-Blocker Use in Older Hospitalized Patients Affected by Heart Failure and Chronic Obstructive Pulmonary Disease: An Italian Survey From the REPOSI Register.

Beta (ß)-blockers (BB) are useful in reducing morbidity and mortality in patients with heart failure (HF) and concomitant chronic obstructive pulmonary disease (COPD). Nevertheless, the use of BBs could induce bronchoconstriction due to ß2-blockade. For this reason, both the ESC and GOLD guidelines strongly suggest the use of selective ß1-BB in patients with HF and COPD. However, low adherence to guidelines was observed in multiple clinical settings. The aim of the study was to investigate the BBs use in older patients affected by HF and COPD, recorded in the REPOSI register. Of 942 patients affected by HF, 47.1% were treated with BBs. The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge (admission, 36.9% vs. 51.3%; discharge, 38.0% vs. 51.7%). In addition, no further BB users were found at discharge. The probability to being treated with a BB was significantly lower in patients with HF also affected by COPD (adj. OR, 95% CI: 0.50, 0.37-0.67), while the diagnosis of COPD was not associated with the choice of selective ß1-BB (adj. OR, 95% CI: 1.33, 0.76-2.34). Despite clear recommendations by clinical guidelines, a significant underuse of BBs was also observed after hospital discharge. In COPD affected patients, physicians unreasonably reject BBs use, rather than choosing a ß1-BB. The expected improvement of the BB prescriptions after hospitalization was not observed. A multidisciplinary approach among hospital physicians, general practitioners, and pharmacologists should be carried out for better drug management and adherence to guideline recommendations.

Beneficial Effects of Polydeoxyribonucleotide (PDRN) in an In Vitro Model of Fuchs Endothelial Corneal Dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is a bilateral, hereditary syndrome characterized by progressive irreversible injury in the corneal endothelium; it is the most frequent cause for corneal transplantation worldwide. Oxidative stress induces the apoptosis of corneal endothelial cells (CECs), and has a crucial function in FECD pathogenesis. The stimulation of the adenosine A2A receptor (A2Ar) inhibits oxidative stress, reduces inflammation and modulates apoptosis. Polydeoxyribonucleotide (PDRN) is a registered drug that acts through adenosine A2Ar. Thus, the goal of this study was to assess the effect of PDRN in an in vitro FECD model. Human Corneal Endothelial Cells (IHCE) were challenged with H2O2 (200 µM) alone or in combination with PDRN (100 µg/mL), PDRN plus ZM241385 (1 µM) as an A2Ar antagonist, and CGS21680 (1 µM) as a well-known A2Ar agonist. H2O2 reduced the cells' viability and increased the expression of the pro-inflammatory markers NF-κB, IL-6, IL-1ß, and TNF-α; by contrast, it decreased the expression of the anti-inflammatory IL-10. Moreover, the pro-apoptotic genes Bax, Caspase-3 and Caspase-8 were concurrently upregulated with a decrease of Bcl-2 expression. PDRN and CGS21680 reverted the negative effects of H2O2. Co-incubation with ZM241385 abolished the effects of PDRN, indicating that A2Ar is involved in the mode of action of PDRN. These data suggest that PDRN defends IHCE cells against H2O2-induced damage, potentially as a result of its antioxidant, anti-inflammatory and antiapoptotic properties, suggesting that PDRN could be used as an FECD therapy.

Pharmacological Treatment of Diabetic and Non-Diabetic Patients With Coronary Artery Disease in the Real World of General Practice.

Type 2 diabetes mellitus (T2DM) severely increases the probability of developing coronary artery disease (CAD), and diabetic patients with CAD should be considered at very high cardiovascular risk. The complexity of this clinical scenario makes very hard the appropriateness of the pharmacological treatment in the real world. To investigate the implementation of guideline recommendations for the treatment of patients affected by CAD with or without T2DM, a retrospective observational study was carried out between 2018 and 2020, by using the computerized clinical medical record of 10 general practitioners (GPs) including 13,206 subjects. A total of 926 patients (7.0%) were affected by CAD and 393 (42.4%) of them were also diabetic. LDLc, SBP, DBP, and FPG were recorded in 77.4%, 65.4%, 66.5%, and 82.6% of patients, respectively. Comorbidities (median; IQR = 8; 6-10 vs. 5; 3-7: p < 0.001) were significantly high in diabetic patients. Specialist counselling has been observed in 59.9% of diabetic and 57% of non-diabetic patients (p = 0.400). Antithrombotic drugs, statins, ß-blockers, or RAASs were prescribed in 67.2%, 59.6%, and 75.9% of patients, respectively. Overall, 462 (49.9%) patients used the treatment suggested by guidelines. Dyslipidemia, hypertension, atherosclerosis, and specialist counselling were predictors of suggested drugs use both in diabetic and non-diabetic patients. Diabetes was not an independent factor related to the likelihood to be properly treated, according to the guidelines. Glucose lowering drugs were prescribed in 69.5% of diabetic patients, but only 39 (14.3%) were treated with the proper GLP-1 or SGLT2-i, whereas 45 patients (16.5%) received the improper sulphonylureas. Our results showed that a "non-ideal" therapeutic approach was adopted in patients affected by diabetes and CAD. ADA and ESC guidelines recommend the use of at least one hypoglycemic agent belonging to the GLP-1 or SGLT2-i class in diabetic patients with high/very high cardiovascular risk, regardless of the glycemic target (HbA1c <7%). However, only a few diabetic patients on hypoglycemic therapy were appropriately treated. These data suggest that a closer collaboration between the GPs, clinical pharmacologist, and specialists is needed in the real world scenario of the general practice in order to effectively improve adherence to guidelines and overall management of global cardiovascular risk in diabetic patients.

Polydeoxyribonucleotide: A Promising Biological Platform to Accelerate Impaired Skin Wound Healing.

The normal wound healing process is characterized by a complex, highly integrated cascade of events, requiring the interactions of many cell types, including inflammatory cells, fibroblasts, keratinocytes and endothelial cells, as well as the involvement of growth factors and enzymes. However, several diseases such as diabetes, thermal injury and ischemia could lead to an impaired wound healing process characterized by wound hypoxia, high levels of oxygen radicals, reduced angiogenesis, decreased collagen synthesis and organization. Polydeoxyribonucleotide (PDRN) has been used to improve wound healing through local and systemic administration thanks to its ability to promote cell migration and growth, angiogenesis, and to reduce inflammation on impaired wound healing models in vitro, in vivo and clinical studies. In light of all these observations, the aim of this review is to provide a full overview of PDRN applications on skin regeneration. We reviewed papers published in the last 25 years on PubMed, inserting "polydeoxyribonucleotide and wound healing" as the main search term. All data obtained proved the ability of PDRN in promoting physiological tissue repair through adenosine A2A receptor activation and salvage pathway suggesting that PDRN has proven encouraging results in terms of healing time, wound regeneration and absence of side effects.

Management of High Cardiovascular Risk in Diabetic Patients: Focus on Low Density Lipoprotein Cholesterol and Appropriate Drug Use in General Practice.

This study aimed to evaluate the management of high cardiovascular risk (CVr) in the patients with diabetes by exploring the prescribing behavior in a setting of general practitioners (GPs). A retrospective cohort study was carried out using the data recorded between 2018 and 2020 in the clinical database of 10 GPs. Diabetes was defined using the International Classification of Diseases (ICD-9-CM) coding (250*) or using the laboratory parameters (hyperglycemia condition: ≥126 mg/dL). A cohort was described stratifying by demographic, clinical and therapeutic characteristics, and laboratory tests. Both the CVr and statin prescriptions were evaluated; adherence to statin therapy (medication possession ratio, MPR ≥ 80) was calculated in accordance with the low-density lipoprotein cholesterol (LDL-C) target. The multivariate logistic regression models with adjusted odds ratios (ORs) and the corresponding 95% Confidence Intervals (CIs) were calculated to identify the predictors of lipid modifying agents use and achieved target therapy; moreover, glucose-lowering drugs use was evaluated. Out of 13,206 people screened, 1,851 (14.0%) patients were affected by diabetes mellitus (DM), and 1,373 were identified at high/very high CVr. Of them, 1,158 (84.3%) had at least one measurement of LDL-C, and 808 (58.8%) received a prescription with at least one lipid-lowering drug (LLD). The patients at high/very high CVr treated or not treated with LLD, reached the LDL-C target in 24.0 and 10.3%, respectively (p < 0.001). Furthermore, 34.6% of patients treated with high intensity LLDs and adherent to therapy showed the LDL-C values below the therapeutic target. Out of 1,373 patients at high/very high CVr, 958 (69.8%) had at least one prescription of glucose-lowering drugs. Of them, 52.0% (n = 498) were prescribed not in agreement with the current guidelines. More specifically, 392 patients (40.9%) were treated with metformin only, while the remaining 106 (11.1%) were treated with metformin together with hypoglycemic agents other than glucagon-like peptide-1 receptor agonists (GLP1-RA) or sodium-glucose-transporter 2 (SGLT2) inhibitors. Our results suggest the urgent need to improve the management of patients with diabetes at high and very high CVr in the real life, to reduce the burden of diabetes on the health system.

Kidney Disease Management in the Hospital Setting: A Focus on Inappropriate Drug Prescriptions in Older Patients.

Aging with multimorbidity and polytherapy are the most significant factors that could led to inappropriate prescribing of contraindicated medications in patients with chronic kidney disease (CKD). The aim of this study was to evaluate the prescriptions of contraindicated drugs in older adults in CKD and to identify their associated factors in a hospital context. An observational retrospective study was carried out considering all patients ≥65 years with at least one serum creatinine value recorded into the REPOSI register into 2010-2016 period. The estimated glomerular filtration rate (eGFR) was applied to identify CKD. A descriptive analysis was performed to compare demographic and clinical characteristics; logistic regression models were used to estimate factors of inappropriate and percentage changes of drug use during hospitalization. A total of 4,713 hospitalized patients were recorded, of which 49.8% had an eGFR <60 ml/min/1.73 m2; the 21.9% were in treatment with at least one inappropriate drug at the time of hospital admission with a decrease of 3.0% at discharge (p = 0.010). The probability of using at least one contraindicated drug was significantly higher in patients treated with more several drugs (OR 1.21, 95% CI 1.16-1.25, p <0.001) and with CKD end-stages (G4: 16.90, 11.38-25.12, p < 0.001; G5: 19.38, 11.51-32.64, p < 0.001). Low-dose acetylsalicylic acid was the contraindicated drug mainly used at the time of admission, reducing 1.2% at discharge. An overall increase in therapeutic appropriateness in hospitalized older patients with CKD was observed, despite a small percentage of therapeutic inappropriateness at discharge that underlines the need for a closer collaboration with the pharmacologist to improve the drug management.

Targeting Adenosine Receptor by Polydeoxyribonucleotide: An Effective Therapeutic Strategy to Induce White-to-Brown Adipose Differentiation and to Curb Obesity.

Obesity is a worldwide chronic metabolic disease characterized by an abnormal fat accumulation and represents one of the main risk factors for several diseases. White adipose tissue is the primary site for energy storage in the form of triglycerides, whereas brown adipose tissue does not store energy-providing lipids but rather dissipates it by producing heat. White-to-brown adipocyte trans-differentiation could represent a new target of anti-obesity strategies and result in fat reduction. Previous studies indicated that adenosine receptor activation induces trans-differentiation of white adipocytes to brown adipocytes. The aim of this study was to evaluate the effects of polydeoxyribonucleotide (PDRN), an A2Ar receptor agonist, in an in vitro model of browning. Mouse 3T3-L1 pre-adipocytes were differentiated in mature adipocytes with specific culture media and then treated with PDRN (10 µg/mL), PDRN + ZM241385 (1 µM), CGS21680 (1 µM) and CGS + ZM241385 for 24 h. Cell viability was studied by MTT assay, and browning induction was evaluated by Oil Red O staining and by RT-qPCR to study gene expression of browning markers. PDRN, as well as CGS21680, reduced the accumulation of lipids, cell volume and lipid droplet size; increased the expression of UCP1, PRDM16 and DIO2, considered as browning markers; and reduced the expression of FASn and FABP4, considered as whitening markers. In addition, PDRN decreased leptin expression and enhanced adiponectin mRNA levels. All these effects were abrogated when PDRN was co-incubated with the A2Ar antagonist ZM241385. In conclusion, these results suggest that PDRN is able to induce the white-to-brown adipose differentiation through A2Ar stimulation. Since PDRN is a safe drug already available in the market for other therapeutic indications, its "anti-obesity" potential warrants investigation in a clinical scenario.

PDRN, a natural bioactive compound, blunts inflammation and positively reprograms healing genes in an "in vitro" model of oral mucositis.

Oral mucositis is a side effect hard to treat following high dose chemotherapy or radiotherapy. Adenosine A2A receptor stimulation blocks NF-κB and boosts the Wnt/ß-catenin signaling, thus blunting inflammation and triggering growth factor codifying genes. Polydeoxyribonucleotide (PDRN) is a registered drug that activates the A2A receptor. Therefore, the aim of this study was to evaluate PDRN effects in an "in vitro" model of oral mucositis induced by prompting an inflammatory phenotype in human gingival fibroblasts (GF) and human oral mucosal epithelial cells (EC). GF and EC were stimulated with LPS (2 µg/ml) alone or in combination with i) PDRN (100 µg/ml); ii) PDRN plus ZM241385 (1 µM) as an A2AR antagonist; iii) CGS21680 (1 µM) as an A2AR agonist. LPS boosted NF-κB, TNF-α and IL-6 expression, decreased IL-10 levels and downregulated both Wnt/ß-catenin, VEGF and EGF expression. PDRN reverted the LPS-induced phenotype as well as CGS21680. Co-incubation with ZM241385 abolished PDRN effects, thus confirming A2A receptor involvement in PDRN mechanism of action. These results suggest that PDRN efficacy may be due to a "dual mode" of action: NF-κB inhibition and Wnt/ß-catenin signaling activation. However, these interesting findings need to be confirmed by animal and clinical studies.

Predictors of morbidity and mortality in patients submitted to cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for ovarian carcinomatosis: a multicenter study.

OBJECTIVES: The aim of this retrospective study is to assess the incidence of morbidity and mortality related to cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) and to evaluate their predictors, in patients with peritoneal metastasis of ovarian origin. METHODS: A retrospective multicenter study was carried out investigating results from eight Italian institutions. A total of 276 patients met inclusion criteria. Predictors of morbidity and mortality were evaluated with univariate and multivariate analysis. RESULTS: Overall morbidity was 71.4%, and severe complications occurred in 23.9% of the sample; 60-day mortality was 4.3%. According to univariate logistic regression models, grade 3-4 morbidity was related to Peritoneal Cancer Index (PCI) (OR 1.06; 95% CI 1.02-1.09; p<0.001), number of intraoperative blood transfusions (OR 1.21; 95% CI 1.10-1.34; p<0.001), Completeness of Cytoreduction (CC) score (OR 1.68; 95% CI 1.16-2.44; p=0.006) and number of anastomoses (OR 1.32; 95% CI 1.00-1.73; p=0.046). However, at the multivariate logistic regression analysis, only the number of intraoperative blood transfusions (OR 1.17; 95% CI 1.5-1.30; p=0.004) and PCI (OR 1.04; 95% CI 1.01-1.08; p=0.010) resulted as key predictors of severe morbidity. Furthermore, using multivariate logistic regression model, ECOG score (OR 2.45; 95% CI 1.21-4.93; p=0.012) and the number of severe complications (OR 2.16; 95% CI 1.03-4.52; p=0.042) were recorded as predictors of exitus within 60 days. CONCLUSIONS: The combination of CRS and HIPEC for treating peritoneal metastasis of ovarian origin has acceptable morbidity and mortality and, therefore, it can be considered as an option in selected patients.

A 7-Years Active Pharmacovigilance Study of Adverse Drug Reactions Causing Children Admission to a Pediatric Emergency Department in Sicily.

Children represent one of the most susceptible groups to adverse drug reactions (ADRs), as a consequence of physiological growth and maturation of different organ systems. The aim of this study was to characterize the frequency, preventability and seriousness of ADRs recorded in the Pediatric Emergency Department (ED) of the University hospital of Messina, in Sicily. All the suspected adverse reactions to drugs and vaccines collected from 2012 to 2018 were selected and then analyzed. Only adverse drug reactions (ADRs) with a probable or possible causality assessment were included, according to the Naranjo Algorithm and the World Health Organization criteria; the preventability assessment using Schumock and Thornton criteria was also carried out. The Medical Dictionary for Regulatory Activities (MedDRA) was used to group ADRs. Of 75,935 admissions to the Pediatric ED, 120 were due to suspected ADRs. The rate of hospital admission due to ADRs (75.8%) was significantly greater than that of patients without ADRs (11.9%). Among pediatric patients with ADRs the median (Q1-Q3) age was 29.5 (12-73.25) months. Most of ADRs were observed in infants and children (43.3% and 41.7%, respectively vs adolescents, 15%). In addition, in children with ADRs, females [41 (14-105)] were older than males [23 (11-45)] (p=0.044). Most adverse reactions were serious (75.8%) and 20.8% were preventable or probably preventable; however, the majority of serious ADRs (93.4%) resulted without sequelae. The reactions were found to be as probable (54.2%) or possible (45.8%). Vaccines (n=63), antibacterials (n=31) and anti-inflammatory medicines (n=14) were the most frequently drugs involved. Organ toxicity mapping due to vaccines was general disorders and administration site conditions (65.1%), nervous disorders (50.2%), cutaneous disorders (35%), followed by gastrointestinal disorders (20.6%). Cutaneous disorders (76%) gastrointestinal (20.7%), general (15.5%), and nervous disorders (8.6%) were the organ toxicity mapping due to drugs. Active pharmacovigilance has an essential role in supporting the development of strategies aimed at intervention to reduce admissions due to ADRs. Our data suggest that ADRs represent the first cause of hospitalization to the Pediatric Emergency Department. Furthermore, according to the literature, vaccines and antibiotics are the most frequent cause of adverse drug reactions in children.

Failure of Achieving Tacrolimus Target Blood Concentration Might Be Avoided by a Wide Genotyping of Transplanted Patients: Evidence from a Retrospective Study.

Precise tacrolimus treatment in transplanted patients is achieved in the clinical setting by performing therapeutic drug monitoring (TDM) and consequently adjusting therapy. The aim of this study was to retrospectively analyze the variability in tacrolimus blood levels throughout 2 years of observation in 75 transplanted patients and to investigate if tacrolimus blood levels correlate with presence of genetic polymorphisms, thus modifying tacrolimus pharmacokinetics. CYP3A5*1 (G6986A), CYP3A4*1B (A392G), CYP3A4*22, ABCB1 (C3435T; C1236T; G2677A/T), SLCO1B1 (T521C), polymorphisms were analyzed. Based on the effect of their genotypes, patients were stratified into 5 groups: (1) reduced tacrolimus metabolism (RM), (2) increased metabolism (IM), (3) transporters polymorphisms (TM), (4) metabolism and transporter polymorphisms (AM) and (5) no mutations (Wild Type, WT). The percentage of the samples out of therapeutic range was significantly higher in the IM group than in the WT group (p = 0.001), as well as compared to the TM group (p = 0.004). Only IM pattern (p = 0.015) resulted as an independent predictor of number of tacrolimus blood levels out of therapeutic range. RM pattern (p = 0.006) was inversely related to the administered dose. Therefore, genotyping could become a standard practice before tacrolimus prescription thus decreasing side effects, increasing efficacy and reducing the economic burden for the national health system.

Anti-obesity drug therapy in clinical practice: Evidence of a poor prescriptive attitude.

Obesity is a worldwide growing problem for the health care systems and its treatment is strongly recommended. Orlistat, naltrexone/bupropion, and liraglutide are approved for weight loss in Italy in patients with a Body Mass Index (BMI) ≥ 30 kg/m2 or ≥ 27 kg/m2 with concomitant diseases. However, the prescription of these drugs is significantly low worldwide. General practitioners (GPs) play a key role in the early diagnosis and appropriate management of obesity. The aim of the study was to investigate the management of obesity and the prescriptive attitude of anti-obesity drugs in a general practice setting. All patients registered in lists of 8 GPs with a recorded diagnosis of obesity or BMI values ≥ 30 kg/m2 in the period 2017-2018, were recruited. A descriptive analysis of demographic and clinical characteristic was carried out. The Spearman's correlation rank test was applied to identify correlations between BMI and all the variables of interest. Among 1301 obese patients, only 66.1 % had been diagnosed and 29.4 % had no registered BMI value. Patients with recorded BMI, were overweight (7.8 %) or in the obesity class I (38.8 %), class II (14.1 %), and class III (7.1 %), respectively. The obese patients (class 1-3) were older [66 (55-76) vs 49 (32-59); p < 0.01], and had more concurrent diseases [5 (3-8) vs 4 (2-6); p < 0.01] than patients who reached a BMI < 30 Kg/m2. Moreover, most of obese were high cardiovascular risk (HCVr) patients (67.0 % vs 31.9 %; p < 0.01). The BMI was directly related to age (rs 0.14; p < 0.01), diabetes (rs 0.19; p < 0.01), hypertension (rs 0.14; p < 0.01), heart failure (rs 0.09; p < 0.01), HCVr (rs 0. 12; p < 0.01) and number of comorbidities (rs 0.08; p = 0.01). No prescriptions of orlistat or naltrexone/bupropion were found. Liraglutide was prescribed only in 7 patients because of the concomitant presence of diabetes. Our results suggest a low adherence to guide line recommendations for obesity management and confirm an under-prescription of anti-obesity drugs in Italy.

Chronic Kidney Disease Management in General Practice: A Focus on Inappropriate Drugs Prescriptions.

Nephrotoxic drugs prescriptions are often prescribed inappropriately by general practitioners (GPs), increasing the risk of chronic kidney disease (CKD). The aim of this study was to detect inappropriate prescriptions in patients with CKD and to identify their predictive factors. A retrospective study on patients with creatinine values recorded in the period 2014-2016 followed by 10 GPs was performed. The estimated glomerular filtration rate (eGFR) was used to identify CKD patients. The demographic and clinical characteristics and drugs prescriptions were collected. A descriptive analysis was conducted to compare the characteristics and logistic regression models to estimate the predictive factors of inappropriate prescriptions. Of 4098 patients with creatinine values recorded, 21.9% had an eGFR <60 mL/min/1.73m2. Further, 56.8% received inappropriate prescriptions, with a significantly lower probability in subjects with at least a nephrologist visit (Adj OR 0.54 (95% CI 0.36-0.81)) and a greater probability in patients treated with more active substances (1.10 (1.08-1.12)), affected by more comorbidities (1.14 (1.06-1.230)), or with serious CKD (G4/G5 21.28 (7.36-61.57)). Nonsteroidal anti-inflammatory drugs (NSAIDs) were the most used contraindicated drugs (48.5%), while acetylsalicylic acid was the most inappropriately prescribed (39.5%). Our results highlight the inappropriate prescriptions for CKD authorized by GPs and underline the need of strategies to improve prescribing patterns.

ß-Caryophyllene Inhibits Cell Proliferation through a Direct Modulation of CB2 Receptors in Glioblastoma Cells.

Glioblastomas are aggressive cancers characterized by uncontrolled proliferation and inflammation. b-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist that showed an important anti-inflammatory effect through the interaction of CB2 and peroxisome proliferator-activated receptor gamma (PPARg) receptors. BCP effects were investigated in an in vitro model of glioblastoma. U-373 and U87, derived from a human glioblastoma, and human glioma stem-like cells (GSCs) were treated with BCP at different doses and time-points. AM360, a specific CB2 antagonist, was added 2 h before BCP treatment. BCP showed a significant anti-proliferative effect, reducing cell viability, inhibiting cell cycle, and increasing apoptosis, as demonstrated by Tunel assay, caspase-3 and caspase -9 activation. In addition, the pro-apoptotic BAX expression was increased, whereas the anti-apoptotic Bcl-2 expression was reduced. Treatment with BCP decreased Beclin-1, LC3 and p62/SQSTM1 expression, indicating a possible switch of autophagy to apoptosis. BCP's anti-inflammatory effect was demonstrated by NF-κB reduction, PPARg activation and TNF-a decrease; BCP significantly reduced Jun N-Terminal Kinase (JNK) expression as a consequence of TNF-α inhibition. AM360 abrogated BCP effects, thus demonstrating the BCP mechanism of action through the CB2 receptor. These findings let us hypothesize that BCP may act as a tumor suppressor in glioblastoma, acting on CB2 receptor and modulating JNK.