Evaluation of the QTc interval during lenvatinib treatment in radioiodine-refractory differentiated thyroid cancer: reports from the real-life clinical practice.

As for other tyrosine kinase inhibitors, a prolongation of ECG-recorded QTc intervals may be observed during lenvatinib treatment; a warning on this phenomenon has been stated. However, methods and frequency of ECG recordings have seldom been reported in this context. We present two cases of patients treated with lenvatinib for radioiodine-refractory differentiated thyroid cancer in whom the QTc interval was long monitored through a weekly 12-lead ECG registration. Overall, the maximum QTc increase above baseline was 3 and 31 ms in the first and second patient, respectively. QTc interval did not reach the toxicity value for drug withdrawal in either of the patients. These data may provide further information on cardiac safety profile of lenvatinib in a real-life practice

Regulation of ob gene expression: evidence for epinephrine-induced suppression in human obesity

Leptin acts as satiety factor and increases energy expenditure. Studies conducted on animals and in vitro on adipocytes culture have shown that infusion of catecholamines leads to a significant reduction of ob gene expression; it appears of interest to evaluate the in vivo effects of adrenergic activation on the expression of the ob gene in humans. We studied ob gene expression in adipose tissue samples from 13 obese subjects before and after epinephrine (25 ng/min x kg ideal body weight for 3 h) and 6 obese patients during saline infusion. Hormonal infusion led to a significant increase in epinephrine plasma levels (from 27 +/- 4 to 339 +/- 75 pg/mL; P < 0.001), plasma free fatty acids (from 0.73 +/- 0.05 to 0.98 +/- 0.07; P < 0.05), heart rate (13.5 +/- 3.1 beats/min; F = 2.9; P < 0.03), and systolic blood pressure (F = 2.7; P < 0.05), whereas diastolic blood pressure did not show significant variation. Plasma leptin levels decreased by the end of the infusion (from 63 +/- 13 to 49 +/- 11 ng/mL; P < 0.05), and ob messenger ribonucleic acid levels were significantly reduced (decrease amounting to 47 +/- 5% of basal values). Our study shows that adrenergic activation contributes to regulate ob messenger ribonucleic acid levels in humans. The interaction between epinephrine and leptin may operate during metabolic and psychological stress to regulate energy expenditure and food intake

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P &lt; .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

Peer reviewe

Adrenomedullary function and its regulation in obesity

Sympathoadrenal system (SAS) represents a major contributor to body homeostasis, regulating blood pressure heart rate, energy balance and intermediary metabolism. Thus, it is not unexpected that in last decades a consistent literature has been focused on the possible role of sympathoadrenal system in the pathogenesis of human obesity. There are, however, many factors confounding comparison of sympathoadrenal system activity between lean and obese subjects. Among these, one should be aware that SAS should be functionally separated into sympathetic nervous system (SNS) and adrenal medulla (AM), and that each of these two systems can be activated independently from the other by distinct physiological stimuli; this phenomenon in fact underlies the discordant pattern of findings for adrenomedullary and sympathetic activity in human obesity. While, in fact, obese subjects often display an increased basal SNS activity, there are numerous reports of blunted AM function in obese. Recent evidence suggests that this reduced adrenaline secretion is an acquired feature of human obesity, a finding that fits in well with the hypothesis that hormonal mileu, particularly sex steroids and cortisol, plays a role in the determination of blunted AM activity. Catecholamines have been recently demonstrated to play a role also in the regulation of whole energy balance. Adrenaline in fact acutely reduces both leptin mRNA as well as circulating leptin in human obese subjects, suggesting that catecholamines may influence the cross-talk between energy stores and the centrally mediated modulation of food intake. In summary, the study of adrenomedullary function and of possible mechanisms of its disturbances in human obesity, appears of great interest, and surely deserves further investigations

Systematic study of long-term stability of 3,4-dihydroxyphenylglycol in plasma for subsequent determination with liquid chromatography

The effect of three storage temperature levels (i.e. +4, -20 and -80degreesC) and time intervals from sampling (3, 6 and 9 months) on the degradation of 3,4-dihydroxyphenylglycol (DHPG) and norepinephrine (NE) was investigated in a systematic study. Extracted human plasma samples and acidified standard solutions were stored for long periods (up to 9 months) without the addition of any stabilizing agent. DHPG and NE values, determined using a ion-pair reversed-phase high-performance liquid chromatography method with electrochemical detection of coulometric type (IP-RP-HPLC-CD), remained constant over time in those plasma samples and standard solutions that had been stored at the lowest storing temperature (i.e. -80degreesC). The expected degradation was observed at higher temperature levels. Plasma and standard DHPG degradation can, therefore, be prevented by storing samples at a lower temperature than previously suggested with no need to add any stabilizing agent

Increasing diversion of prescribed benzodiazepines and Z-drugs to new psychoactive substances

Over the last few years reports have indicated an increase in the number, type and availability of new psychoactive substances belonging to the benzodiazepine class. These molecules may pose high risks to users, since the majority have never undergone clinical trials or tests so their pharmacology and toxicology is largely unknown. However the new drug scenario emerging from the COVID-19 global pandemic seems to play a role in increasing the diversion of prescribed benzodiazepines and Z-drug. A brief presentation of this phenomenon is hereby presented. The awareness and response activities at national and international levels related to this issue should be enforced

Pharmacotoxicology and analytical issues of gamma-hydroxybutyric acid in clinical and forensic laboratory

Gamma-hydroxybutyric acid (GHB) can be considered both an endogenous metabolite and a precursor of the neurotransmitter gamma-aminobutyric acid (GABA) acting within the central nervous system as a neuromodulator. Pharmacologically, GHB is classified as a central nervous system depressant and its mechanism of action involves interaction and binding with GABA-B receptors. With the generic name of sodium oxybate, the sodium salt of GHB, is sold as a pharmaceutical product under the trade name of Xyrem® when prescribed for the treatment of people with narcolepsy and with the name of Alcover® when used to relieve alcohol withdrawal syndrome and treat alcohol dependence. Between the end of the 90s of the twentieth century and the beginning of the twenty-first one, the abuse of GHB became increasingly widespread in the recreational field. The substance, often consumed in combination with alcohol, cannabis, ecstasy (3,4-Methylenedioxymethamphetamine, MDMA), ketamine, has been converted in one of the most used "club drugs", becoming one of the most serious health issues in the emergency department of many European and extra-European Countries because of the initial difficult clinical management of the growing number of cases of intoxication. At the same time, there was an increase of cases of sexual assaults of victims who were unaware they had been given GHB as odourless and colourless sedative substance. In this narrative review, the three different aspects of GHB as endogenous neuromodulator, as prescription drug and as substance of abuse are illustrated. The main methods for qualitative and quantitative analysis in conventional and non-conventional biological matrices for clinical and forensic purposes are also describe

Metabolic effects of fluoxetine in obese menopausal women

Our objective was to assess thermogenic action of fluoxetine (FL) in obese menopausal women, evaluating the effect of FL administration on resting energy expenditure (REE) and on glucose-induced thermogenesis both after acute administration (40 mg in single dose the evening before measurements) and after a 12- week period of diet treatment plus FL (60 mg per day) or placebo. It was a double-blind, placebo-controlled design both in acute and in chronic study. The subjects were 32 obese, otherwise healthy, menopausal women. The patients were assigned randomly to three groups, one performing an acute study protocol, in which resting and glucose-induced thermogenesis was measured after FL and placebo administration, performed in randomised order. The other two groups underwent dietary plus pharmacological treatment (FL or placebo, FL). Resting and glucose-induced thermogenesis was measured at baseline and after 12 weeks of treatment. The results showed that acute FL administration caused an increase in resting energy expenditure (PL: 5.35+/-0.18 vs FL: 5.53+/-0.24 KJ/min, p&lt;0.05). A significant decrease of REE was observed in the PL group after 12 weeks (p&lt;0.03), while a slight, but not significant, decrease was observed in the FL group (p=NS). FL did not affect thermic response to oral glucose neither after acute nor chronic administration (p=NS for all groups studied). The conclusion was that our data give support to thermogenic actions of FL after acute administration, suggesting also that chronic FL treatment may restrain to some degree the metabolic adaptation expected during weight loss in obese subjects. At variance with what observed with other drugs, such as dexfenfluramine, an increased thermic effect of oral glucose does not seem to be involved in the thermogenetic action of FL

Cardiovascular and catecholamine response to clonidine in obese subjects

OBJECTIVE: To investigate central alpha-2 adrenergic activity, one of the main inhibitory factors affecting norepinephrine secretion, in human obesity. DESIGN: Cardiovascular and catecholamine responses to clonidine (300 mu g per os) were evaluated in a group of obese subjects. SUBJECTS: 10 obese men (OM) and 14 obese women (OW). MEASUREMENTS: Mean arterial pressure, pulse rate, plasma norepinephrine (NE) and epinephrine (E) before and 120', 130', 140' after clonidine (CL) administration. RESULTS: The mean arterial pressure decreased after CL administration in obese patients (from 92 +/- 12 to 79 +/- 2 mmHg; P &lt; 0.001) with no significant differences between OM and OW. The values of pulse rate were reduced in obese patients after clonidine (60 +/- 1 b/min vs 65 +/- 1 b/min before clonidine; P &lt; 0.01) with no differences between OM and OW. Plasma E was not affected by the administration of clonidine and no sex related differences were found in the basal (OM: 0.23 +/- 0.03 vs OW: 0.15 +/- 0.03 nmol/L; P = NS) and in the post-CL E levels (OM: 0.22 +/- 0.02 vs OW: 0.14 +/- 0.03 nmol/L; P = NS). Basal plasma NE values were not different between OM (1.32 +/- 0.15 nmol/L) and OW (1.03 +/- 0.11 nmol/L; P = NS). Plasma NE decreased after CL in obese patients (from 1.20 +/- 0.10 to 0.59 +/- 0.08 nmol/L; P &lt; 0.001) and a significant difference was found in the post-CL values between OM and OW (0.74 +/- 0.11 vs 0.40 +/- 0.06 nmol/L respectively; P &lt; 0.01). The decrease in plasma NE was strongly correlated with the basal value of NE (r = 0.70; P &lt; 0.001). The sex-related differences in plasma NE responses to clonidine in obese subjects did not differ with those previously observed in control subjects (P = NS). CONCLUSION: The cardiovascular and catecholamine response to CL in obese patients were similar to that previously observed in normal subjects, indicating a normal alpha-a adrenergic activity. The sex related difference in the NE response to CL, previously reported in normal subjects, was maintained in obese patients