Coronary calcifications as a new prognostic marker in COVID-19 patients: role of CT.

OBJECTIVE: COVID-19 pneumonia, caused by the virus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), was declared a pandemic by the WHO on 11th March 2020. While Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) represents the diagnostic gold standard of infection, computed tomography (CT) has been shown to have an important role in supporting the diagnosis, quantifying the severity, and assessing the efficacy of treatment and its response. Coronary artery calcification (CAC) is a CT finding that estimates atherosclerosis and can be quantified using the coronary artery calcium score (CACS). The purpose of this study is to demonstrate the correlation between coronary artery calcification and mortality rate in COVID-19 patients. PATIENTS AND METHODS: Three hundred seventeen (317) hospitalized patients with SARS-CoV-2 infection were ruled in this retrospective study. All patients underwent a non-ECG-gated chest CT to evaluate lung parenchymal involvement. In the same cohort, we observed the two main coronary arteries (common trunk, circumflex, anterior interventricular and right coronary heart) using a visual score, so patients were divided into four groups based on Ordinal CAC Score (OCS) levels. RESULTS: The multivariate analysis proved that the OCS value was statistically correlated with the mortality rate (p < 0.001). In fact, in the group of patients with an OCS value of 0, the mortality rate was 10.1% (10/99 patients), in the group with OCS between 1 and 4 was 18.9% (21/111), in the OCS group of patients ranged from 5 to 8 was 30.4% (24/79) and in the OCS group between 9 and 12 was 46.4% (13/28). CONCLUSIONS: We suggest that calcific atheromasia of the coronary arteries in patients with COVID-19 can be considered a prognostic marker of clinical outcome.

Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats.

Weight gain is an important side effect of most atypical antipsychotic drugs such as olanzapine. Moreover, although many animal models with metabolic side effects have been well defined, the interaction with other pathways has to be considered. The endocannabinoid system and the CB1 receptor (CB1R) are among the most promising central and peripheral targets involved in weight and energy balance. In this study we developed a rat model based 15-days treatment with olanzapine that shows weight gain and an alteration of the blood parameters involved in the regulation of energy balance and glucose metabolism. Consequently, we analysed whether, and by which mechanism, a co-treatment with the novel CB1R neutral antagonist NESS06SM, could attenuate the adverse metabolic effects of olanzapine compared to the reference CB1R inverse agonist rimonabant. Our results showed alterations of the cannabinoid markers in the nucleus accumbens and of orexigenic/anorexigenic markers in the hypothalamus of female rats treated with olanzapine. These molecular modifications could explain the excessive food intake and the resulting weight gain. Moreover, we confirmed that a co-treatment with CB1R antagonist/inverse agonist compounds decreased food intake and weight increment and restored all blood parameters, without altering the positive effects of olanzapine on behaviour. Furthermore, rimonabant and NESS06SM restored the metabolic enzymes in the liver and fat tissue altered by olanzapine. Therefore, CB1 receptor antagonist/inverse agonist compounds could be good candidate agents for the treatment of weight gain induced by olanzapine.

Solid lipid nanoparticle preparation by a warm microemulsion based process: influence of microemulsion microstructure.

Warm microemulsions (WME) containing lipids are used as starting systems to obtain solid lipid nanoparticles (SLN) in alternative processes to those based on high pressure homogenization technique. SLN characteristics can be influenced by the microemulsion composition and the specific conditions adopted in the quenching process related to the transformation of WME into nanoparticles. To establish optimized conditions for the production of SLN starting from WME, in a first step of this work we have defined the microstructure of warm microemulsions highlighted in the lecithin (LCT)/water (W)/tripalmitin (TP)/1-butanol (B)/taurocholate sodium salt (ST) phase behavior at 70°C. Moreover, we have further studied the LCT/W/TP/B system by evaluating the effect on the microemulsion area due to the LCT/B weight ratio, the replacement of 1-butanol with different alcohols (ROH), and the addition of taurocholate sodium salt (ST) at different LCT/ST weight ratios. The microstructure of the isotropic phase region obtained in the presence of ST has been characterized by both (1)H NMR PGSE measurements and electrical conductivity. The characteristics of final nanoparticles are discussed taking into account both the microstructure of the parent WME and the conditions of the quenching process leading to SLN. The present results highlight the relevance of the microstructural characteristic of WME to assure the obtainment of SLN with average diameter in the order of 100-2000 nm and narrow size distribution.

Losartan and amlodipine on myocardial structure and function: a prospective, randomized, clinical trial.

AIMS: To compare the effects of losartan and amlodipine on myocardial structure and function in hypertensive patients with Type 2 diabetes and left ventricular hypertrophy. METHODS: After a 4-week placebo period, patients were randomized to losartan 50 mg (n = 90) or amlodipine 5 mg (n = 91) for 12 months, with a doubling of the dose in patients who did not respond after 4 weeks. Blood pressure was measured in the clinic every month, while conventional echocardiography and acoustic densitometry (integrated backscatter analysis) were performed at the end of the placebo period and after 12 months of treatment. RESULTS: Both drugs reduced systolic/diastolic blood pressure to a comparable extent. Losartan significantly reduced left ventricular mass index (-19%, P < 0.001), interventricular septal thickness (-16.6%, P < 0.01) and left ventricular posterior wall thickness in diastole (-13.7%, P < 0.01). Amlodipine also decreased such measurements (-10%, P < 0.01 for left ventricular mass index, -9.3%, P < 0.05 for interventricular septal thickness in diastole and -10.1%, P < 0.05 for posterior wall thickness in diastole), but to a lesser extent than losartan. Both drugs significantly increased the ratio of peak filling velocity at early diastole to that at atrial contraction (E/A ratio) and decreased isovolumetric relaxation time: +13.7% and -8.5% with losartan,(both P < 0.01), and +7.9% and -4.9%, with amlopidine (both P < 0.05). Losartan, but not amlodipine, significantly reduced the relative integrated backscatter compared to baseline of the intraventricular septum (-10%, P < 0.01), and of the left ventricular posterior wall (-12%, P < 0.01), while increasing the cyclic variation of integrated backscatter of both the intraventricular septum (+35%, P < 0.001) and the left ventricular posterior wall (+32%, P < 0.001). CONCLUSIONS: Losartan provided a greater attenuation of left ventricular hypertrophy than amlodipine, seemingly as a result of a greater reduction of myocardial fibrosis.

Effects of aliskiren on QT duration and dispersion in hypertensive patients with type 2 diabetes mellitus.

AIM: To evaluate the effect of aliskiren compared to amlodipine on QT duration and dispersion in hypertensive patients with type 2 diabetes. METHODS: A total of 170 outpatients aged 50-75 years with mild to moderate hypertension (SBP >130 and <180 mmHg and DBP >80 and <100 mmHg) and type 2 diabetes were randomly treated with aliskiren 300 mg or amlodipine 10 mg, both given once daily for 24 weeks, according to a prospective, open label, blinded-end point, parallel group design. At the end of the placebo run-in, and after 12, and 24 weeks of treatment blood pressure (BP) measurements (by mercury sphygmomanometer, Korotkoff I and V), plasma biochemistry and a standard 12-lead surface ECG were evaluated. RESULTS: Both aliskiren and amlodipine significantly reduced systolic blood pressure (SBP)/diastolic blood pressure (DBP) values (-27.2/-14.3 mmHg, p < 0.001 vs. placebo and -27.8/-14.2 mmHg, p < 0.001 vs. placebo, respectively), with no statistical difference between the two drugs. Aliskiren, but not amlodipine, significantly reduced maximum QT interval (QTmax) (-14 ms at 12 weeks and -17 ms at 24 weeks, both p < 0.05 vs. placebo) and corrected QT max (QTc max) (-26 ms and -31 ms, p < 0.01) as well as the dispersion of both QT (-11 ms and -13 ms, p < 0.01) and QTc (-18 ms and -19 ms, p < 0.01). CONCLUSIONS: Despite similar BP lowering effect, aliskiren, but not amlodipine, reduced QT duration and dispersion, which might be related to the ability of aliskiren to interfere with mechanisms underlying myocardial electrical instability in the heart of diabetic hypertensive patients.

Different effects of aliskiren and losartan on fibrinolysis and insulin sensitivity in hypertensive patients with metabolic syndrome.

The aim of this study was to compare the effect of aliskiren and losartan on fibrinolysis and insulin sensitivity (IS) in hypertensive patients with metabolic syndrome. After 2-week placebo period, 76 outpatients with mild to moderate hypertension and metabolic syndrome were randomized to aliskiren 300 mg od or losartan 100 mg od for 12 weeks. Clinic blood pressure (BP), plasma PAI-1 antigen, and tPA activity were evaluated after 2, 4, 8, and 12 weeks of treatment. At the end of each treatment period patients performed an euglycemic hyperinsulinemic clamp and IS was assessed by glucose infusion rate (GIR). Both aliskiren and losartan induced a significant and similar SBP/DBP reduction (-15.6/10.7 mmHg and -15.5/10.5 mmHg, p<0.001 vs. baseline, respectively). Both drugs decreased PAI-1 antigen and activity after 2 weeks of treatment; subsequently, only the decreasing effect of aliskiren was sustained throughout the 12 weeks [-7.5 ng/ml (-31%) p<0.05 vs. baseline], while with losartan PAI-1 increased at week 12 [+3.6 ng/ml (+15%), p<0.05 vs. baseline and p<0.01 vs. aliskiren)]. The tPA activity showed no significant change with aliskiren and a decrease with losartan [-0.04 IU/ml (-8%), p<0.05 vs. baseline and p<0.01 vs. aliskiren]. Aliskiren significantly increased GIR [+1.4 mg/min/kg (+28%), p<0.01 vs. baseline] while losartan did not change it [+0.2 mg/min/kg (+4%), NS vs. baseline, p<0.05 vs. aliskiren)]. These results indicated that in this type of patients, despite similar BP reduction, aliskiren improved the fibrinolytic balance as well as IS, while losartan worsened the fibrinolytic balance and did not affect IS. The clinical relevance of these different effects remains to be clarified.

Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia.

BACKGROUND: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene and the p27(KIP1) encoding gene CDKN1B have been associated with two well-defined hereditary conditions, familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 4 (MEN4). Somatotropinomas are present in most AIP mutated FIPA kindreds, as well as in two-thirds of MEN4 patients who carry pituitary tumors. METHODS: Germline DNA samples of 131 Italian sporadic acromegalic patients including 38 individuals with multiple tumors, and of six FIPA families (four homogeneous for prolactinomas and two heterogeneous with prolactin/nonfunctioning pituitary adenomas) were collected in a multicentric collaborative study. The prevalence of AIP and CDKN1B gene point mutations and copy number variations were evaluated. RESULTS: Two novel (IVS3+1G>A and c.871G>A) and one previously described (c.911G>A) AIP mutations were detected in four apparently sporadic cases (3.1%) with relatively high age at diagnosis (49+/-18, range 30-67). No mutations/rearrangements were detected in FIPA families. The highly conserved c.871G>A substitution was detected in a patient who also carried a MEN1 mutation suggesting that she is a double heterozygote. The possible pathogenic effect on AIP splicing of the silent substitution c.144G>A found in another patient was ruled out using a minigene-based approach. CDKN1B mutations/rearrangements were neither identified in patients with multiple neoplasia nor in FIPA families. CONCLUSION: AIP is mutated in about 3% of apparently sporadic acromegalic patients. The relatively high age at diagnosis, as well as its sporadic presentation, suggests that these patients are carriers of mutations with reduced pathogenicity. p27(KIP1) is unlikely to represent the common unifying nonendocrine etiology for acromegaly and cancer.

Antinociceptive activity of Delta9-tetrahydrocannabinol non-ionic microemulsions.

Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the major psychoactive constituent of Cannabis sativa L., has been widely studied for its potential pharmaceutical application in the treatment of various diseases and disturbs. This sparingly soluble terpeno-phenolic compound is not easy to handle and to be formulated in pharmaceutical preparations. The aim of this work was to develop a stable aqueous Delta(9)-THC formulation acceptable for different ways of administration, and to evaluate the therapeutic properties of the new Delta(9)-THC based preparation for pain treatment. Due to the thermodynamic stability and advantages of microemulsion based systems, the study was focused on the identification of aqueous microemulsion based systems containing Delta(9)-THC. Oil in water Delta(9)-THC microemulsions were individuated through phase diagrams construction, using the non-ionic surfactant Solutol HS15, being this surfactant acceptable for parenteral administration in human. A selected microemulsion samples containing 0.2 wt% of Delta(9)-THC, stable up to 52 degrees C, was successfully assayed on animal models of pain. Significant antinociceptive activity has been detected by both intraperitoneal and intragastric administration of the new Delta(9)-THC pharmaceutical preparation. The effect has been highlighted in shorter time if compared to a preparation of the same active principle based on previously reported conventional preparation.

1-(2',4'-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice.

Neuropathic pain is a devastating neurological disease that seriously affects quality of life in patients. The mechanisms leading to the development and maintenance of neuropathic pain are still poorly understood. However, recent evidence points towards a role of spinal microglia in the modulation of neuronal mechanisms. In this context, cannabinoids are thought to modulate synaptic plasticity as well as glial functions. Here, we have investigated the effect of chronic treatment with a selective agonist of cannabinoid type 2 receptor (CB2), 1-(2',4'-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyrazole-3 carboxamide (NESS400), on pain thresholds in the spared nerve injury (SNI) model in the mouse and on the distribution and activation of spinal microglia. Repeated treatment with NESS400 (4 mg/kg) significantly alleviated neuropathic mechanical allodynia and thermal hyperalgesia. In the dorsal horn (L4-L6) of neuropathic mice microglia activation (quantification of the length of microglial processes) and astrocytosis were associated with CB2 receptor over-expression on both cell types. Treatment with NESS400 significantly reduced the number of hypertrophic microglia while leaving microglial cell number unaffected and reduced astrogliosis. Moreover, prolonged administration of NESS400 reduced mRNA expression of pro-inflammatory markers and enhanced anti-inflammatory marker gene expression in dorsal horn extracts. In conclusion, we show that selective CB2 receptor stimulation prevents thermal hyperalgesia, alleviates mechanical allodynia and facilitates the proliferation of anti-inflammatory microglial phenotype in the ipsilateral dorsal horn of the spinal cord in SNI mice.

A comparison of continuous subcutaneous paliperidone infusion and repeated subcutaneous injection of risperidone free-base in rats.

It is proposed that to achieve a therapeutic effect in schizophrenia patients, dopamine D(2)-receptor occupancy by antipsychotics within the striatum must exceed 60-65%. However, at high levels of D(2)-receptor occupancy, the risk of extrapyramidal symptoms (EPS) is increased. Following oral dosing of antipsychotics, peaks and troughs in plasma drug concentrations may be mirrored by fluctuations in D(2)-receptor occupancy. Paliperidone, a novel antipsychotic available as extended-release tablets (paliperidone ER), is the major active metabolite of risperidone and exhibits a plasma pharmacokinetic profile with reduced peak-trough fluctuations and consistent D(2)-receptor occupancy compared with conventional oral antipsychotic formulations. Using formulations that resemble those in clinical practice, this study provides a preclinical evaluation of the pharmacological properties of paliperidone ER and risperidone immediate-release formulation in terms of consistent antipsychotic efficacy over time and extrapyramidal symptom liability. Significant fluctuations in inhibition of d-amphetamine-induced hyperlocomotion were observed for repeated subcutaneous (SC) risperidone injections, whereas stable inhibitory efficacy was demonstrated during continuous SC paliperidone infusion. Similarly, significant fluctuations in latency on-bar were observed with repeated SC risperidone injections, whereas significantly lower latency on-bar was demonstrated following continuous SC paliperidone infusion. These results in an animal model suggest that although risperidone and paliperidone demonstrate similar pharmacologic effects, continuous administration of paliperidone achieves more stable antipsychotic efficacy with reduced motor impairment, akin to the effects observed with paliperidone ER in clinical studies.

Comparative effects of telmisartan and eprosartan on insulin sensitivity in the treatment of overweight hypertensive patients.

The aim of this study was to compare the effect of telmisartan and eprosartan on insulin sensitivity in overweight hypertensive patients. Fifty overweight (BMI > or = 25 and <30 kg/m (2)) outpatients, aged 41-65 years, with mild to moderate hypertension [systolic blood pressure (SBP) >140 and diastolic blood pressure (DBP) > or = 90 and < or = 110 mmHg], after a 4-week placebo period, were randomized to receive telmisartan 80 mg or eprosartan 600 mg for 8 weeks. Following another 4-week placebo period, patients were crossed to the alternative regimen for further 8 weeks. At the end of each placebo and active treatment period, blood pressure (BP), insulin sensitivity (by euglycemic hyperinsulinemic clamp), fasting plasma glucose (FPG), insulin (FPI), total cholesterol (TC), LDL-C, HDL-C, and triglycerides (Tg) were evaluated. Insulin sensitivity was expressed as the amount of glucose infused during the last 30 min (glucose infusion rate, GIR) in micromol/min/kg. Both telmisartan and eprosartan significantly reduced SBP/DBP values (by a mean of 19.4/13.3 mmHg and 17.9/12.1 mmHg respectively, all p<0.001 vs. placebo), with no significant difference between the two treatments. GIR was significantly increased by telmisartan (2.25+/-0.61 micromol/min/kg, p<0.05 vs. placebo) but not by eprosartan (0.25+/-0.14 micromol/min/kg, p=ns), the difference between the two drugs being statistically significant (p<0.02). No change in FPG, FPI, HDL-C, and Tg was observed with either treatment. Telmisartan significantly reduced TC (-9.9 mg/dl, -5%, p<0.04 vs. placebo) and LDL-C (-8.8 mg/dl, -7%, p<0.03 vs. placebo), whereas eprosartan did not influence them. These findings indicate a superiority regarding an improvement of insulin sensitivity and plasma lipid profile in overweight hypertensives by telmisartan as compared to eprosartan, possibly related to the selective stimulating PPAR-gamma property of telmisartan.

Effect of valsartan addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients.

The aim of this study was to assess the effect of valsartan addition to amlodipine on ankle foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP), two objective measures of ankle oedema. After a 4-week placebo period, 80 grade 1-2 hypertensive patients (diastolic blood pressure (DBP)>90 mm Hg and <110 systolic blood pressure (SBP)>140 mm Hg) were randomized to amlodipine 10 mg or valsartan 160 mg or amlodipine 10 mg plus valsartan 160 mg for 6 weeks according to an open-label, blinded end point, crossover design. At the end of the placebo period and of each treatment period, blood pressure, AFV and PSTP were evaluated. AFV was measured using the principle of water displacement. PSTP was assessed connecting the subcutaneous pretibial interstitial environment with a water manometer. Both amlodipine and valsartan monotherapy significantly reduced SBP (-16.9 and -14.5 mm Hg, respectively, P<0.01 vs baseline), and DBP (-12.9 and -10.2 mm Hg, respectively, P<0.01 vs baseline) but the reduction was greater with the combination (-22.9 mm Hg for SBP, P<0.01 vs monotherapy; -16.8 mm Hg for DBP, P<0.01 vs monotherapy). Amlodipine monotherapy significantly increased both AFV (+23%, P<0.01 vs baseline) and PSTP (+75.5%, P<0.001 vs baseline) whereas valsartan monotherapy did not influence them. As compared to amlodipine alone, the combination produced a less marked increase in AFV (+6.8%, P<0.01 vs amlodipine) and PSTP (+23.2%, P<0.001 vs amlodipine). Ankle oedema was clinically evident in 24 patients with amlodipine and in six patients with the combination. These results suggest that angiotensin receptor blockers partially counteract the microcirculatory changes responsible for calcium channel blockers induced oedema formation.

Effect of telmisartan/hydrochlorothiazide vs lisinopril/hydrochlorothiazide combination on ambulatory blood pressure and cognitive function in elderly hypertensive patients.

The aim of this study was to compare the effects of telmisartan/hydrochlorothiazide (HCTZ) vs lisinopril/HCTZ combination on ambulatory blood pressure and cognitive function in elderly hypertensive patients. A total of 160 patients, 76 men and 84 women, aged 61-75 years, with sitting diastolic blood pressure (DBP)>90 mmHg and <110 mmHg and systolic blood pressure (SBP)>140 mmHg were randomized to receive temisartan 80 mg/HCTZ 12.5 mg o.d. or lisinopril 20 mg/HCTZ 12.5 mg o.d. for 24 weeks, according to a prospective, open-label, blinded end point, parallel-group design. At the end of a 2-week wash-out period and after 12 and 24 weeks of active treatment, 24-h noninvasive ambulatory BP monitoring (ABPM) was performed and cognitive function was evaluated through six different tests (verbal fluency, Boston naming test, word-list memory, word-list recall, word-list recognition and Trails B). Both treatments significantly reduced ambulatory BP. However, the telmisartan/HCTZ combination produced a greater reduction in 24-h, day-time and night time ABPM values. Lisinopril/HCTZ did not induce significant changes in any of the cognitive function test scores at any time of the study, whereas at both 12 and 24 weeks telmisartan/HCTZ significantly improved the word-list memory score (+17.1 and +15.7%, respectively, P<0.05 vs baseline), the word-list recall score (+13.5 and +16.9%, P<0.05) and the Trails B score (-33 and -30.5%, P<0.05). These results suggest that in elderly hypertensive patients treatment with telmisartan/HCTZ produces a slightly greater reduction in ambulatory BP than lisinopril/HCTZ combination and, unlike this latter, improves some of the components of cognitive function, particularly episodic memory and visuospatial abilities.

Long-term effects of ramipril and nitrendipine on albuminuria in hypertensive patients with type II diabetes and impaired renal function.

The aim of this study was to compare the effects of ramipril and nitrendipine chronic treatment on urinary albumin excretion (UAE) in hypertensive patients with type II non-insulin-dependent diabetes mellitus (NIDDM) and impaired renal function. A 2-year, prospective, randomised study was conducted on 51 men with a diastolic blood pressure (DBP) > or =95 and < or =105 mm Hg, stable NIDDM, serum creatinine between 1.6 and 3.0 mg/dl and persistent UAE >300 and <2000 mg/24 h. After a 3-month preliminary observation period, during which patients began a low-protein, low-sodium diet, and a subsequent 4-week run-in period on placebo, patients were randomly treated with ramipril 5 mg or nitrendipine 20 mg for 2 years. Both drugs similarly reduced BP without affecting glucose homeostasis. In the ramipril group UAE significantly decreased after only 3 months of treatment, whereas in the nitrendipine group a significant although lesser reduction in UAE was observed only after 1 year. During the second year the UAE% change was not statistically different between the two treatments. Serum creatinine and creatinine clearance showed no significant change with both drugs. The progression of renal insufficiency as assessed by the rate of reduction of creatinine clearance over the 2 years of the study was similar in the ramipril and the nitrendipine groups. In conclusion both ramipril and nitrendipine were associated with a decrease in UAE although such a reduction was earlier and more marked with ramipril. The decline of renal function did not differ significantly between the two treatments.

Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive patients.

AIMS: The aim of this study was to compare the effects of the ACE-inhibitor lisinopril and the angiotensin II receptor antagonist losartan on insulin sensitivity in the treatment of non diabetic hypertensives. METHODS: Twenty-five non diabetic subjects with mild to moderate hypertension, 11 females and 14 males, aged 44-63 years, after a 4-week wash-out period on placebo, were randomized to receive lisinopril 20 mg once daily or losartan 50 mg once daily for 6 weeks. Following another 4-week wash-out period, patients were crossed to the alternative regimen for further 6 weeks. At the end of the placebo and of the active treatment periods, blood pressure (BP) was measured (by standard mercury sphygmomanometer, Korotkoff I and V) and insulin sensitivity was assessed by the euglycaemic hyperinsulinaemic clamp technique. Glucose infusion rate (GIR) during the last 30 min of clamp and total glucose requirement (TGR) were evaluated. RESULTS: Both lisinopril and losartan significantly reduced SBP (by a mean of 20.2 and 17.2 mmHg, respectively) and DBP (by a mean of 15.2 and 12.3 mmHg, respectively), with no difference between the two treatments. GIR, used as an indicator of insulin sensitivity, was significantly increased by lisinopril (+1.5 mg min(-1) kg(-1), P<0.05 vs baseline) but not by losartan (+0.42 mg min(-1) kig(-1), NS), the difference between the two drugs being statistically significant (P<0.05). TGR was increased by lisinopril (+7.3 g, P<0.05 vs baseline), whereas losartan did not significantly modify it (+1.9 g, NS). CONCLUSIONS: In conclusion, with all cautions due to an absence in this study of a randomized placebo phase, our findings suggest that lisinopril improved insulin sensitivity whereas losartan did not affect it.

ACE inhibition but not angiotensin II antagonism reduces plasma fibrinogen and insulin resistance in overweight hypertensive patients.

The aim of this study was to compare the effects of the angiotensin-converting enzyme (ACE) inhibitor perindopril and the angiotensin II antagonist losartan on insulin sensitivity and plasma fibrinogen in overweight hypertensive patients. Twenty-eight overweight mild to moderate [diastolic blood pressure (DBP) >90 and <110 mm Hg] hypertensives aged 43-64 years, after a 4-week placebo period, were randomized to perindopril, 4 mg o.d., or losartan, 50 mg o.d., for 6 weeks. Then, after a new placebo period, patients were crossed to the alternative regimen for further 6 weeks. At the end of the placebo and of the treatment periods, blood pressure was measured, plasma fibrinogen was evaluated, and insulin sensitivity was assessed by the euglycemic, hyperinsulinemic clamp technique. Glucose infusion rate (GIR) during the last 30 min of clamp and total glucose requirement (TGR) were evaluated. Both perindopril and losartan reduced SBP (by a mean of 20.2 mm Hg, p < 0.001 vs. placebo; and 15.8 mm Hg, p = 0.002 vs. placebo, respectively) and DBP (by a mean of 15.2 mm Hg, p = 0.001 vs. placebo, and 11.8 mm Hg, p = 0.01 vs. placebo respectively), with no difference between the two treatments. GIR was significantly increased by perindopril (+2.91 mg/min/kg, p = 0.042 vs. placebo), but not by losartan (+0.28 mg/min/kg, NS). TGR was not modified by losartan but was increased by perindopril (+9.3 g, p = 0.042 vs. placebo). Plasma fibrinogen levels were reduced by perindopril (-53.4 mg/dl, p = 0.022 vs. placebo) but not by losartan (-16.8 mg/dl, NS). The perindopril-induced decrease in fibrinogen was correlated with the increase in GIR (r = 0.39; p < 0.01). These findings suggest that fibrinogen decrease produced by the ACE inhibitor is related to its action on insulin sensitivity, which seems to be dependent not on angiotensin II blockade but rather on other mechanisms.

Comparative effects of nebivolol and atenolol on blood pressure and insulin sensitivity in hypertensive subjects with type II diabetes.

The aim of this double-blind, parallel group study was to compare the effects of nebivolol and atenolol on blood pressure (BP) and insulin sensitivity in hypertensive patients with type II, non-insulin dependent diabetes mellitus (NIDDM). After a 4-week run-in period on placebo, 30 patients (14 males and 16 females) aged 43 to 69 years, with stable NIDDM and mild to moderate hypertension (DBP > or =95 and <116 mm Hg) were randomised to receive either nebivolol 5 mg or atenolol 50 mg, both administered once daily for 6 months. At the end of the placebo and the active treatment periods, supine and standing BP was measured, 24-h urinary C-peptide, HbA1c, plasma glucose and lipid levels were evaluated and an euglycaemic hyperinsulinaemic clamp was performed to evaluate insulin sensitivity: glucose infusion rate during the last 60 min of clamp and total glucose requirements were evaluated. Nebivolol 5 mg once daily was of an equivalent efficacy as atenolol 50 mg once daily at reducing supine and standing systolic and diastolic BP values. Neither beta-blocker adversely affected carbohydrate metabolism in terms of insulin sensitivity, whole body glucose utilization, HbA1c and 24-h urinary C-peptide excretion. No significant changes in cholesterol (total, high density and low density lipoprotein) and triglycerides plasma levels were observed with both beta-blockers. These findings indicate that, in hypertensive patients with NIDDM, ie, in subjects who have established insulin resistance, treatment with nebivolol and atenolol neither further deteriorated insulin sensitivity nor adversely affected the lipid profile.

Epidemiology of known diabetes in Lombardy, north Italy. Clinical characteristics and methodological aspects.

Diabetes epidemiology can benefit in Italy from the large network of outpatient diabetic clinics and patients' facilities. A large investigation was carried out in 1988, in a certain area of northern Italy, to estimate the prevalence of known diabetes. Using four information sources, 4547 distinct patients were identified. Through the capture-recapture method we assessed completeness and estimated a prevalence of 3.3%. Prevalence of type 1 diabetes was 0.8 per 1000. Italian age-standardised overall prevalence and developed-world standardised rates were 2.8% and 2.6%, respectively. A representative sample of 2358 patients was characterised through a standard questionnaire. Women were diagnosed about 6 years later than men (58.8 +/- 0.4 vs 52.9 +/- 0.4, P < 0.0001), while the duration of the disease was very similar in both sexes (9.9 +/- 0.2 vs 9.5 +/- 0.2). As regards diabetes therapy, 17.2% of the patients were on diet alone, 62.1% on oral agents and 20.6% on insulin. Among the insulin-treated subjects more than half were on adjuvant therapy with tablets, and only 6.2% were treated with 3 injections/day. Less than half of all the known diabetic subjects had had an ophthalmoscopic examination in the previous 2 years.

Ketanserin effects on insulin sensitivity in nonobese, nondiabetic hypertensive patients: an evaluation by the euglycemic-hyperinsulinemic clamp technique.

The aim of this study was to assess the effects of ketanserin on insulin resistance in nondiabetic hypertensive patients. Eleven nonobese, nondiabetic mild to moderate hypertensives (6 males, 5 females, aged 39-59 years), after a 4 week run-in period on placebo, were treated with ketanserin 40 mg twice daily for 12 weeks. Blood pressure (BP) (by standard mercury sphygmomanometer) and insulin sensitivity (by the euglycemic hyperinsulinemic clamp technique) were evaluated at the end of the placebo period and at the end of the treatment period. Ketanserin produced a significant decrease in BP (from 160 +/- 13/100 +/- 4 mmHg to 146 +/- 10/89 +/- 5 mmHg p < 0.01). The amounts of exogenous glucose required to hold glucose levels constant during clamp were not changed by ketanserin as compared to placebo 34.5 +/- 3.5 g vs 33.8 +/- 3.1 g). The rate of glucose infusion required during the last 60 minutes of the clamp, used as an indicator of insulin sensitivity, was not different before and after treatment (5.52 +/- 0.41 mg/min/ kg vs 5.21 +/- 0.39mg/min/kg). These results suggest that in nonobese, nondiabetic hypertensive patients ketanserin monotherapy is effective in reducing BP values without affecting insulin sensitivity.