Effect of neridronate in osteopenic patients after heart, liver or lung transplant: a multicenter, randomized, double-blind, placebo-controlled study.

BACKGROUND: Transplantation (Tx) is an effective therapeutic option in patients with end-stage organ failure and osteoporosis and related fractures are a recognized complication in these patients. Aim of this study was to evaluate the efficacy of neridronate in patients with reduced bone mass after Tx of the heart, liver or lung. METHODS: In this multicenter randomized double-blind controlled trial (RCT), 22 patients were treated with neridronate (25 mg i.m./month) and 17 received placebo. All patients received daily oral calcium (500 mg) and vitamin D (400 IU). Dual-energy X-ray absorptiometry (DXA) was evaluated at 0, 6 and 12 months and markers of bone turnover at 0, 3, 6, 9 and 12 months. RESULTS: Thirty-nine patients (11 heart Tx, 21 liver Tx, 7 lung Tx), aged 49.3±9.1 years, with a T-score <-2.0 SD at lumbar spine or femoral level were included. In neridronate-treated patients, a significant increase in lumbar bone mineral density (BMD) was observed after 12 months vs. placebo control (0.92±0.13 g/cm2 vs. 0.84±0.08 g/cm2; P=0.005). Femur and hip BMD remained unchanged between groups. Total alkaline phosphatase, bone alkaline phosphatase and beta-cross-laps significantly decreased over the 12 months in neridronate-treated patients vs. placebo, respectively (107.4±74 U/L vs. 157.6±107.1 U/L, P=0.002; 5.7±3.3 µg/L vs. 11.7±4.3 µg/L, P<0.001 and 0.25±0.13 ng/mL vs. 0.73±0.57 ng/mL, P<0.001). No difference was observed between neridronate and placebo groups regarding safety profile. CONCLUSIONS: This is the first RCT that demonstrates the efficacy of neridronate in increasing bone density and reducing bone turnover in organ Tx recipients with significant skeletal morbidity.

Long-term effect of oxycodone/naloxone on the management of postoperative pain after hysterectomy: a randomized prospective study.

BACKGROUND: The analgesic efficacy of oxycodone prolonged-release (PR) combined with naloxone PR (OXN) in postoperative pain management is recognized, however, few studies have examined the efficacy of OXN on pain relief and bowel function following hysterectomy. This study compared the effect of OXN vs. standard treatment for post-operative pain management and bowel function following hysterectomy. METHODS: This randomized prospective study included 83 women who underwent laparoscopic/laparotomic hysterectomy. General anesthesia was induced by propofol (1.5-2 mg/kg), fentanyl (50-100 µg) and rocuronium (0.6-1 mg/kg) and maintained with sevoflurane (MAC 0.8-1) and fentanyl (1-2 µg/kg). Intraoperative analgesia was performed with ketorolac (30 mg), paracetamol (1 g) and morphine (0.1 mg/kg). Postoperative analgesia in the control group (N.=41) included morphine (0.2-0.4 mg/kg/day), whereas the OXN (N.=42) group only received oxycodone (10 mg)/naloxone (5 mg) for the first 48 hours. As rescue analgesic, both groups received paracetamol (3 mg). Bowel Function Index (BFI) and pain numeric rating scales (NRS) were measured at day 0, 1, 2, 3, 5 and 7, whereas vital parameters, rescue medication and side effects were recorded for the first three days only. RESULTS: Bowel function indices were significantly improved in OXN-treated patients at all time points compared to morphine-treated patients. Mean static pain NRS was significantly decreased at day 2 and day 3 and dynamic pain NRS at day 3 in the OXN group. Side effects, rescue analgesic and antiemetics were more frequent in the control group. CONCLUSIONS: Improved pain control, bowel function and reduced side effects were observed with OXN compared to morphine in patients who underwent hysterectomy.

Clinical management of nondialysis patients with chronic kidney disease: a retrospective observational study. Data from the SONDA study (Survey Of Non-Dialysis outpAtients).

BACKGROUND: A lack of awareness of chronic kidney disease (CKD) often results in delayed diagnosis and inadequate treatment. PURPOSE: The objective of this study was to assess the therapeutic management and outcome of nondialysis CKD patients. METHODS: Three hundred ninety-seven patients (54.9% males aged 67.5 ± 14.6 years) were retrospectively screened at the Nephrology Department, GB Grassi Hospital, Rome, Italy. After a baseline visit, patient data were collected every 6 months for a total of 24 months. Clinical characteristics were measured at baseline, then the following outcomes were measured every 6 months: staging of CKD, presence of concomitant diseases, treatment and adherence to Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines for anemia management. RESULTS: Three hundred sixty-eight (92.7%) patients attended at least one visit and 92 (23.2%) patients attended all four visits. Patients were mainly referred to a nephrologist for chronic renal failure (61.7%) or hypertension (42.8%). At baseline, 79.6% of patients had previous hospitalization and 79.1% were receiving antihypertensive medication. Serum creatinine and/or glomerular filtration rate was examined in >90% of patients, whereas parathyroid hormone was rarely examined (5.5%). Vitamin D supplementation was received by 6.5% of patients. The majority of patients were staged at 3 or 4 CKD (32% and 23.9%, respectively) and did not significantly change over time. The use of antithrombotic, antilipidemic and erythropoietin medication increased over the four surveys. The majority of patients (86.8%) achieved hemoglobin K/DOQI target levels. CONCLUSION: These findings demonstrate a current lack of attention of CKD and related disorders (mineral metabolism, electrolyte balance, and anemia) at the level of the general practitioner (GP) and non-nephrology specialist, which can result in both delayed referral and inadequate treatment. By increasing both awareness of CKD and the coordinated relationship between GPs and nephrologists, patient clinical and therapeutic outcome may be improved.

Efficacy and safety of delapril/indapamide compared to different ACE-inhibitor/hydrochlorothiazide combinations: a meta-analysis.

The main objective of this meta-analysis was to compare the efficacy of the combination of delapril and indapamide (D+I) to different angiotensin-converting enzyme inhibitor (ACEi) plus hydrochlorothiazide (HCTZ) combinations for the treatment of mild-to-moderate hypertension. A secondary objective was to examine the safety of these two combinations. Studies comparing the efficacy of D+I to ACEi+HCTZ combinations in hypertensive patients and published on computerized databases (1974-2010) were considered. Endpoints included percentage of normalized patients, of responders, change in diastolic and systolic blood pressure (DBP/SBP) at different time-points, percentage of adverse events (AEs), and percentage of withdrawal. Four head-to-head randomized controlled trials (D+I-treated, n = 643; ACEi+HCTZ-treated, n = 629) were included. Meta-analysis indicated that D+I-treated patients had a higher proportion with normalized blood pressure (P = 0.024) or responders (P = 0.002) compared to ACEi+HCTZ-treated patients. No difference was observed between treatments on absolute values of DBP and SBP at different time-points. Although the rate of patients reporting at least one AE was similar in both groups (10.4% versus 9.9%), events leading to study withdrawal were lower in the D+I group versus the ACEi+HCTZ group (2.3% versus 4.8%, respectively; P = 0.018). This meta-analysis suggests that treatment with D+I could provide a higher proportion of normalized or responder patients with good tolerability compared to ACEi+HCTZ combinations.

Use of carvedilol in hypertension: an update.

ß-blockers are effective antihypertensive agents and, together with diuretics, have been the cornerstone of pioneering studies showing their benefits on cardiovascular morbidity and mortality as a consequence of blood pressure reduction in patients with hypertension. However, evidence from recent meta-analyses have demonstrated no benefit afforded by atenolol compared with placebo in risk of mortality, myocardial infarction, or stroke, and a higher risk of mortality and stroke with atenolol/propranolol compared with other antihypertensive drug classes. Thus, the effect of these agents on cardiovascular morbidity and mortality in hypertensive patients, especially their use in uncomplicated hypertension, has remained largely controversial. However, it is recognized that the clinical studies used in these meta-analyses were mainly based on the older second-generation ß-blockers, such as atenolol and metoprolol. Actually, considerable heterogeneity in, eg, pharmacokinetic, pharmacological, and physicochemical properties exists across the different classes of ß-blockers, particularly between the second-generation and newer third-generation agents. Carvedilol is a vasodilating noncardioselective third-generation ß-blocker, without the negative hemodynamic and metabolic effects of traditional ß-blockers, which can be used as a cardioprotective agent. Compared with conventional ß-blockers, carvedilol maintains cardiac output, has a reduced prolonged effect on heart rate, and reduces blood pressure by decreasing vascular resistance. Studies have also shown that carvedilol exhibits favorable effects on metabolic parameters, eg, glycemic control, insulin sensitivity, and lipid metabolism, suggesting that it could be considered in the treatment of patients with metabolic syndrome or diabetes. The present report provides an overview of the main clinical studies concerning carvedilol administered as either monotherapy or in combination with another antihypertensive or more frequently a diuretic agent, with particular focus on the additional benefits beyond blood pressure reduction.

Differentiation of hippocampal stem cells into functional neurons: evolving our understanding of monoamine oxidase-A inhibition.

Depression affects many millions of people worldwide and much is still unknown with respect to the mode of action of antidepressant drugs. The hippocampus has been associated with many psychiatric disorders, including clinical depression. Recently, stem cells have also been shown to reside within discrete regions of the hippocampus and can differentiate under a variety of conditions into neural cells. In this issue, Chiou et al. have elegantly demonstrated that cells isolated from the rat hippocampus, and treated with the antidepressant moclobemide, may be differentiated in vitro into neural cells exhibiting features to those of serotoninergic neurons. They have also suggested that this process was mediated, in part, through the expression of specific antiapoptotic genes (Bcl-2 and Bcl-XL) and via activation of extracellular-regulated kinase. This work raises the attractive possibility that the use of antidepressants, such as moclobemide, may exert neuroprotective and potentially neurogenerative effects not just in vitro, but also in vivo, through the selected differentiation of stem cells into functional neurons. The exact mechanisms by which such antidepressants differentiate neural stem cells still remains to be fully elucidated.

PDGF-induced signaling in proliferating and differentiated vascular smooth muscle: effects of altered intracellular Ca2+ regulation.

OBJECTIVE: Platelet-derived growth factor-BB (PDGF)-induced intracellular signaling is involved in phenotypic modulation of vascular smooth muscle (VSM). This study has examined the PDGF-induced Ca2+ increase and the resultant effect on signaling pathways in proliferative compared with fully differentiated VSM. METHODS: PDGF-induced changes in Ca2+ were measured in portal vein (PV) myocytes from 2-4-day-old (proliferating), compared to 6-week-old (differentiated), Sprague Dawley rats. Phospholipase C (PLC)gamma expression and activation of extracellular signal-regulated kinase (ERK) 1/2 was determined by immunoblotting or confocal immunolabelling. Activation of the Ca(2+)-dependent transcription factor, nuclear factor of activated T-cells (NFATc), was assessed by electromobility shift assay. RESULTS: PDGF increased the intracellular Ca2+ concentration in differentiated, but not in proliferating, PV myocytes. This is probably due to very low expression of PLC(gamma) in proliferating PV. In 6-week-old PV, PDGF stimulation induced nuclear translocation and activation of NFATc. PDGF did not induce NFATc activation in neonatal PV. PDGF-induced ERK1/2 activation was observed in both 2-4-day-old and 6-week-old PV. In 6-week-old PV, ERK1/2 activation was Ca(2+)-dependent and protein kinase C-dependent. However in 2-4-day-old PV, PDGF-induced ERK1/2 activation was via a Ca(2+)-independent, atypical protein kinase C. PLC(gamma) expression was also decreased in the neointima, compared to media, of balloon-injured rabbit subclavian arteries. CONCLUSIONS: The regulation of PDGF-induced Ca2+ increases by PLC(gamma) expression in VSM may provide a mechanism for coordinating different signaling pathways leading to activation of specific transcription factors. This may play an important role in the phenotypic modulation of VSM.

Endothelin-1- and depolarization-induced differential regulation of cAMP response element-binding protein in proliferating and developed vascular smooth muscle.

Regulation of the transcription factor cAMP response element-binding protein (CREB) is important for gene expression in vascular smooth muscle (VSM). This study has examined the intracellular regulation of CREB by endothelin-1 (ET-1) and depolarization in native VSM, comparing proliferative and fully differentiated phenotypes. Portal veins from neonatal (proliferative) and 6-week-old (differentiated) rats were stimulated with ET-1 or K(+). In both phenotypes, CREB activation was increased by ET-1 although the time course was prolonged in neonatal VSM. This paralleled a prolonged ET-1-induced [Ca(2+)](i) increase. ET-1-induced CREB activation was dependent on extracellular signal-regulated kinase 1/2 (ERK1/2) activation and inhibited by BAPTA but not by a calmodulin-dependent protein kinase (CamK) inhibitor. In contrast, CREB activation induced by depolarization in both neonatal and developed VSM was significantly reduced by CaMK inhibition and by ERK1/2 inhibition. Therefore, CREB activation is regulated differentially in VSM depending upon stimulus; however, this is not altered in different growth states.

Pathophysiology of vascular dysfunction in a rat model of chronic joint inflammation.

The impact of chronic joint inflammation on articular vascular function in rats was investigated to address whether joint swelling and the associated vascular dysfunction are dependent upon a common prostanoid mechanism. Urinary nitrate/nitrite (NO(x)) and PGE(2) excretion, knee joint diameter and body weight were measured following induction of adjuvant-induced arthritis (AIA). Ten days postinduction of AIA, joint vascular reactivity was assessed by measuring the perfusion response using a laser Doppler imager (LDI) to topical application of acetylcholine (ACh) and sodium nitroprusside (SNP). Four groups were compared: a non-inflamed control group and three AIA groups treated i.p. with vehicle, indomethacin or SC-236 (at equimolar doses). The selective cyclooxygenase-2 (COX-2) inhibitor (SC-236) was used to differentiate between COX-1 and -2-derived prostaglandins. Urinary NO(x) and PGE(2) levels increased substantially during the early phase of AIA but decreased thereafter. Toxicity to indomethacin but not SC-236 was observed, as indicated by a marked decrease in body weight. Joint swelling was similarly attenuated by indomethacin and SC-236 (P= 0.0001 cf. vehicle-treated AIA; n= 5-6 per group), indicating that this is due to COX-2 and not COX-1 inhibition. The AIA-induced changes in urinary NO(x) and PGE(2) were corrected by both COX inhibitors. While vascular reactivity to ACh and SNP was significantly attenuated by AIA (P < 0.002; n= 5-10 per group), the perfusion responses to these vasodilating agents were similar in all three AIA groups, demonstrating that the vascular dysfunction was not corrected by inhibition of either COX-1 or COX-2 enzymes. Furthermore, the attenuation of both ACh and SNP-induced responses in AIA suggest that vascular dysfunction was not exclusively endothelial in nature. In conclusion, the joint swelling and vascular dysfunction associated with AIA appear to be mediated, at least in part, by independent mechanisms. While COX-1/COX-2 inhibition reduced joint swelling, vascular dysfunction in AIA is independent of constitutive or inducible prostanoid mechanisms, and appears not to be solely endothelial-derived, but to involve other components such as the vascular smooth muscle.

Pathophysiological basis of acute inflammatory hyperaemia in the rat knee: roles of cyclo-oxygenase-1 and -2.

The role of different isoforms of cyclo-oxygenase (COX) in mediating the acute (0-6 h) and late (24 h) phases of inflammation was investigated in the rat knee joint following intra-articular injection of carrageenan. The hyperaemic response was assessed transcutaneously using laser Doppler imaging (LDI). Samples were taken at corresponding time points for detection of synovial COX-1, COX-2 and inducible nitric oxide synthase (iNOS) mRNA, and measurement of urinary prostaglandin (PG) and nitric oxide metabolites (NO(x)). A non-selective COX inhibitor (indomethacin, 15 mg kg(-1) I.P.), a selective COX-2 inhibitor (SC-236, 16.8 mg kg(-1) I.P.) or vehicle were administered 1 h prior to carrageenan in the acute phase study. LDI scans were taken hourly for 4 h post-induction. Inflammatory hyperaemia in the vehicle group was attenuated in the indomethacin- (P < 0.001, two-way ANOVA) and SC-236-treated groups (P < 0.0001), with no difference between these treatments. At 24 h, I.V. infusion of indomethacin (0.1 mg min(-1)), increased vascular resistance (24 +/- 7.1 %; P < 0.05) compared to vehicle infusion, whereas SC-236 (0.11 mg min(-1)) did not. Resistance changes to indomethacin also differed from SC-236 (P < 0.05). Knee joint diameter progressively increased over 24 h (P < 0.0001, one-way ANOVA). Urinary PG levels increased by 6 h (P < 0.05), but returned to baseline by 24 h. COX-1 mRNA was detectable at all time points; COX-2 mRNA only at 3 h. Urinary NO(x) levels increased progressively over 24 h (P < 0.05), paralleled by induction of iNOS in the 3 and 24 h samples. Prostaglandin production via COX-2 appears to mediate the development of acute inflammatory hyperaemia, but nitrergic mechanisms may supervene subsequently. COX-1 but not COX-2 contributes to the maintenance of basal blood flow in the hyperaemic joint at 24 h.