Multicenter Observational/Exploratory Study Addressed to the Evaluation of the Effectiveness and Safety of Pharmacological Therapy in Opioid-Dependent Patients in Maintenance Therapy in Southern Italy.

A multicenter-observational study was performed to assess the effectiveness of rac-methadone, levomethadone, and buprenorphine in opioid-dependent patients in polytherapy in Southern Italy. The primary endpoint was the reduction of urinary positivity to the substances and the maintaining doses. Patients (N = 266, age = 44.80 ± 5.65, male = 79.70%, female = 20.30%) have been recruited. At recruitment, 75% of them were on treatment with rac-methadone, levomethadone, and buprenorphine/naloxone. The patients were grouped into three clusters. The levomethadone patients of Cluster A (N patients = 211), after 180 days, showed stability in urinary methadone positivity, with a marked decrease in heroin -53 ± 4%, cannabinol's -48 ± 2%, and cocaine -37 ± 6% positivity, with no differences between treatments. A lower QTcF value of 426 ± 8.4 ms was recorded in the levomethadone patients (delta = -19 ms) vs. rac-methadone, at significantly lower doses of levomethadone (-34%, -50.2% in males) (p < 0.05). The Cluster B data were collected from 37 patients, with a high prevalence of comorbidity infections (HIV/HCV/HPV), monitored for 21 months during COVID-19. High doses of levomethadone (58.33 ± 31.58 mg/day) were needed to stabilize those that were negative for opioids and cannabinoids, in contrast to the rac-methadone and buprenorphine/naloxone patients that showed positive toxicology. Eighteen patients of the Cluster C in double diagnosis (major depressive 38.90%, bipolar 27.78%, and schizophrenia 16.67%) were stabilized with high doses of racemate 97.5 ± 8 mg/day, 51.8 ± 5 mg/day of levomethadone (-46.8% vs. rac-methadone; -71% in men), and 2.5 ± 1 mg/day of buprenorphine/naloxone. Three patients in remission were treated with tapering doses of levomethadone. Significantly reduced QTcF values were recorded with levomethadone (delta -32 ms vs. rac-methadone) in the bipolar patients, as well as the schizophrenia patients in remission (delta -45.19 ms vs. rac-methadone). Our patients were safely stabilized. Levomethadone, compared to the racemate, contributes to reducing the illicit use, especially of opioids and cannabinoids at significantly lower doses with cardiovascular safety, which, in bipolar patients, is clinically significant.

Impaired cognitive executive dysfunction in adult treated hypertensives with a confirmed diagnosis of poorly controlled blood pressure.

BACKGROUND: High blood pressure (BP) poses a major risk for cognitive decline. Aim of the study was to highlight the relationship between cognitive assessment scores and an effective therapeutic BP control. METHODS: By medical visit and ambulatory BP monitoring (ABPM), we studied 302 treated hypertensives, subdivided according to office/daytime BP values into 120 with good (GC) and 98 poor (PC) BP control, 40 with "white coat hypertension" (WCH) and 44 a "masked-hypertension" phenomenon (MH). Patients underwent neuropsychological assessment to evaluate global cognitive scores at the Mini Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) and attention/executive functions (Delayed Recall, Digit Span Forwards, Digit Span Backwards, Selective Attention, Verbal Fluency, Stroop Test and Clock Drawing). Carotid intima-media thickness (IMT) served as the index of vascular damage. RESULTS: There were no differences among the groups in terms of gender, age, education, metabolic assessment, clinical history and hypertension treatment. GC presented lower office and ambulatory BP values and IMT. PC performed worse than GC on global executive and attention functions, especially executive functions. In PC, office systolic BP (SBP) was significantly associated to the MMSE and FAB scores and, in particular, to Verbal Fluency, Stroop Errors and Clock Drawing tests. Office diastolic BP (DBP) was associated to Selective attention, nocturnal SBP to Digit Span backwards and Verbal Fluency. Worse cognitive assessment scores were obtained in WCH than GC. CONCLUSIONS: The findings showed that in adult treated hypertensives, a poor BP control, as both doctor's office and daytime scores, is associated to impaired global cognitive and especially executive/attention functions.

Effect of clustering of metabolic syndrome factors on capillary and cerebrovascular impairment.

BACKGROUND: Hypertension and metabolic disorders, attended by impaired microcirculation, represent major risk factors for cerebrovascular impairment, as well as being individual components of the metabolic syndrome (MetS). Aim of the study was to establish whether mild hypertensives, aged ≤65years, may be affected by progressive microvascular damage impairing cerebrovascular perfusion, related to a progressive clustering of MetS components. METHODS: Twenty-two normotensives with no MetS component (NTN-0), 29 hypertensives with no (HTN-0), 30 with one (HTN-1), 29 with two (HTN-2), 27 with three (HTN-3), 25 with all four (HTN-4) MetS components, were recruited. The study required office and twenty-four hour ambulatory blood pressure monitoring and video capillaroscopy. Functional (fCD), anatomical (aCD) and recruited (RECR) phalangeal skin capillarity were assessed. Cerebral vasodilatory reserve was measured by the breath-holding index (BHI), using transcranial Doppler, in HTN-1 and HTN-2 with MetS. RESULTS: The fCD and aCD were reduced in hypertensives and progressively reduced in those with MetS, while RECR was also impaired. BHI was lower in HTN-2 than in HTN-1 (p<0.001). BHI was correlated with fCD in HTN-1 (.396, p: .046), HNT-2 (.497, p: .011), and with aCD in HTN-2 (.494, p: .012), by partial Pearson test. DISCUSSION: The findings show that hypertensives exhibit an increasing microvascular rarefaction with MetS progression and that an impaired cerebral perfusion occurs when the MetS is established. The data underline the importance of preventing MetS in mild hypertensives, as it causes microvascular damage and impairs cerebral arterial perfusion.

Microvascular impairment is associated with insulin resistance in euglycemic mild hypertensives.

BACKGROUND: Hypertension and diabetes are significantly associated with insulin resistance (IR), which could affect the vasodilatory capacity and microcirculation. The aim of the study was to verify whether IR is associated with a reduced microvascular blood flow in normoglycemic mild hypertensives. METHODS: Eighty-four untreated grade-1 hypertensives were equally divided, according to the IR homeostasis model assessment (HOMA) index, into three groups: IR-Low = 2.16 +/- 0.09 vs. IR-Medium = 3.77 +/- 0.09 vs. IR-High = 7.08 +/- 0.68 (P < 0.001) with similar sex distribution, office systolic blood pressure (SBP)/diastolic blood pressure (DBP) and history of hypertension. They underwent ambulatory blood pressure monitoring (ABPM) and a laboratory stress session, during which blood pressure (BP), heart rate (HR), and skin blood flow (Laser Doppler) were taken on the forehead (LDF) and the hand (LDH), where the neuroadrenergic control of the microvascular blood flow is higher. Reactivity was calculated as "area-under-the-curve" (AUC) during arithmetic and cold pressor tests. Postischemic LDH served as the index of endothelial microcirculatory damage. RESULTS: ABPM confirmed the diagnosis of hypertension, but IR-High patients showed a reduced nighttime BP fall. They also demonstrated reduced LDH-AUC and LDF-AUC although BP-AUC and HR-AUC reactivity were similar. Postischemic LDH was lower in the IR-High group (P < 0.05), and the postischemic LDH change was progressively impaired in both IR-Medium and IR-High patients (P < 0.001). LDH-AUC (-0.305, P = 0.007) and postischemic LDH at 30 s (-0.217, P = 0.059) and 60 s (-0.248, P = 0.030) during hyperemia were associated with HOMA. Multiple regression analysis, with HOMA as the dependent variable, showed that BMI (beta = 0.336, P < 0.001) and LDH (beta = -0.239, P < 0.001), LDH-AUC (beta = -0.296, P < 0.01) and postischemic LDH change (beta = -0.321, P < 0.001) entered the equation. CONCLUSIONS: The findings suggest that IR is associated with functional microvascular constrictive impairment in normoglycemic mild hypertensives.

Measures of total stress-induced blood pressure responses are associated with vascular damage.

BACKGROUND: The role of cardiovascular reactivity to study hypertension, and the assessment methods, are still controversial. We aimed to verify the association of hypertension and vascular damage with several measures of cardiovascular response. METHODS: We studied 40 patients with normal-high (132 +/- 1/87 +/- 1 mm Hg) blood pressure (Group 1) and 80 untreated hypertensive subjects. Postischemic forearm vascular resistance (mFVR) served to differentiate hypertensive subjects (142 +/- 2/92 +/- 1 mm Hg v 143 +/- 2/94 +/- 2 mm Hg, P = NS) with a lower (Group 2) and higher (Group 3) hemodynamic index of vascular damage (4.8 +/- .05 v 6.3 +/- .09, P < .001). Reactivity was induced by Stroop (5') and cold pressor (90") tests. We measured muscular contraction and skin conductance as indices of emotional arousal, blood pressure, heart rate, forearm blood flow, and vascular resistance. Reactivity measures included: a) change from baseline, b) residualized score, c) cumulative change from baseline and residualized score, and d) total reactivity as area-under-the-curve (AUC), including changes occurring during baseline and recovery phases. RESULTS: The AUC of systolic blood pressure, diastolic blood pressure, and mFVR progressively increased in the groups (P < .001). Corrections of anthropometric and metabolic confounders were introduced in the Pearson equation between mFVR and reactivity measures. The AUC of SBP, DBP, and forearm blood flow and resistance demonstrated the highest (P < .001) correlation. On multiple regression analysis, AUC of SBP (beta = 0.634) and forearm blood flow (beta = -0.337) were predictive (P < .001) of vascular damage. CONCLUSIONS: Total blood pressure stress response, as AUC, including baseline and recovery phases, was significantly better associated with hypertension and vascular damage than the other reactivity measures studied.

Stress-induced hemodynamic responses are associated with insulin resistance in mild hypertensives.

BACKGROUND: High blood pressure (BP) and pulse pressure (PP) are recognized as independent risk factors for cardiovascular diseases, whereas insulin resistance (IR) is often associated with hypertension. The purpose of the study was to verify whether PP, taken at the doctor's office and during laboratory stimuli, might be predictive of IR. METHODS: Homeostasis model assessment insulin resistance index (HOMA) was calculated in 75 grade 1 hypertensives (148 +/- 2/92 +/- 1 mm Hg). Then, patients underwent hemodynamic reactivity study, induced by color word stroop, cold pressor, and handgrip tests. Stress response was calculated as total area (value x time) - baseline area (baseline value x time). RESULTS: Patients with similar age, history of hypertension, blood lipids and office blood pressure, but different HOMA (IR-low: 36.3 +/- 1.7 v IR-medium: 62.6 +/- 1.6, P <.001; IR-high: 123.1 +/- 12.8, P <.001 v IR-low and IR-medium), were divided in tertiles. They demonstrated a significant reactivity of systolic BP (IR-low: 225 +/- 58 v IR-medium: 448 +/- 43, P <.01; IR-high: 625 +/- 55, P <.001 v IR-low and P <.01 v IR-medium), PP (IR-low: -8 +/- 19 v IR-medium: 83 +/- 13, P <.001; IR-high: 201 +/- 19, P <.001 v IR-low and IR-medium), and stroke volume (SV) (IR-low: -138 +/- 43 v IR-medium: 1 +/- 27, P <.01; IR-high: 28 +/- 24, P <.001 v IR-low), but similar arterial stiffness (PP/SV) response. Partial correlation between IR and hemodynamic measurements showed a significant association only for systolic BP (0.54, P <.001), PP (0.686, P <.001), and SV (0.384, P <.001) reactivity, but not for office and baseline values. Stepwise multiple regression showed that only PP (beta: 0.634, P <.001) and, among hemodynamic determinants, SV (beta: 0.401, P <.001) response entered into the equation. CONCLUSIONS: The findings demonstrate that increased stress-induced PP, maintained by SV response, is the most predictive hemodynamic variable of reduced insulin sensitivity in mild hypertensives.